1 00:00:05,750 --> 00:00:07,160 - I'm Dr. Nelson Scottsdale. 2 00:00:07,160 --> 00:00:11,890 Welcome to the fourth day of the 42nd Annual Darwin Festival 3 00:00:11,890 --> 00:00:13,940 here at Salem State University. 4 00:00:13,940 --> 00:00:17,600 And what I'd like to do now is turn the webinar 5 00:00:17,600 --> 00:00:21,470 over to my colleague, Dr. Sheila Schreiner, 6 00:00:21,470 --> 00:00:24,340 who will introduce today's speaker. 7 00:00:24,340 --> 00:00:25,340 Thank you very much. 8 00:00:27,290 --> 00:00:30,050 - Good morning, before I introduce this morning's speaker, 9 00:00:30,050 --> 00:00:31,690 I just wanna remind the audience 10 00:00:31,690 --> 00:00:33,870 of a couple of housekeeping items. 11 00:00:33,870 --> 00:00:35,940 If you do get kicked out of the webinar, 12 00:00:35,940 --> 00:00:39,470 you can use the same link that you used to enter to rejoin. 13 00:00:39,470 --> 00:00:42,560 Also, we're gonna hold questions until the end, 14 00:00:42,560 --> 00:00:44,730 but you are more than welcome to ask questions 15 00:00:44,730 --> 00:00:47,440 through the Q and A function that's found on the bottom bar. 16 00:00:47,440 --> 00:00:49,650 Okay, so you can enter those questions in 17 00:00:49,650 --> 00:00:51,830 at any point during the presentation, 18 00:00:51,830 --> 00:00:53,820 but again, we will be holding those till the end, 19 00:00:53,820 --> 00:00:56,730 till our speaker has concluded their presentation. 20 00:00:56,730 --> 00:00:59,100 Lastly, there is closed caption available. 21 00:00:59,100 --> 00:01:02,930 So if you click the link for live transcript, 22 00:01:02,930 --> 00:01:05,880 you can turn that on or off. 23 00:01:05,880 --> 00:01:08,570 Okay, so I have the honor of introducing, 24 00:01:08,570 --> 00:01:10,850 actually, a classmate of mine from grad school. 25 00:01:10,850 --> 00:01:13,063 Our speaker is Dr. Cecelia Yates. 26 00:01:13,930 --> 00:01:15,950 She's an associate professor 27 00:01:15,950 --> 00:01:18,970 at the Department of Health Promotion and Development, 28 00:01:18,970 --> 00:01:20,300 which is part of the School of Nursing 29 00:01:20,300 --> 00:01:21,900 at the University of Pittsburgh. 30 00:01:21,900 --> 00:01:24,679 She also holds a secondary appointment 31 00:01:24,679 --> 00:01:27,810 for the Department of Pathology in the School of Medicine 32 00:01:27,810 --> 00:01:32,600 at the McGowan Institute of Regenerative Medicine. 33 00:01:32,600 --> 00:01:35,720 Dr. Yates attended to Tuskegee University 34 00:01:35,720 --> 00:01:40,090 where she earned her BS in Biology and Chemistry. 35 00:01:40,090 --> 00:01:43,620 She then obtained her PhD at the University of Pittsburgh, 36 00:01:43,620 --> 00:01:45,520 where she was a classmate of mine. 37 00:01:45,520 --> 00:01:47,560 Over the past 15 years, 38 00:01:47,560 --> 00:01:50,678 she has experience in fibroblast, chemokines, 39 00:01:50,678 --> 00:01:53,098 and extracellular matrix biology 40 00:01:53,098 --> 00:01:58,098 in the pathogenicity of organ fibrosis. 41 00:01:58,150 --> 00:02:01,290 Her research focuses on the understanding of immune cells 42 00:02:01,290 --> 00:02:04,950 and stromal cell mediated interactions to contribute 43 00:02:04,950 --> 00:02:07,690 to the pathogenicity of fibrotic diseases 44 00:02:07,690 --> 00:02:11,220 such as scleroderma and IPF. 45 00:02:11,220 --> 00:02:15,400 Her research group combines both translational 46 00:02:15,400 --> 00:02:18,490 and clinical models to develop therapies, 47 00:02:18,490 --> 00:02:23,160 including biometric peptides, cellular transplantation, 48 00:02:23,160 --> 00:02:28,160 and bio reactive scaffolds to promote tissue regeneration. 49 00:02:28,630 --> 00:02:33,250 She's also a co-founder and a chief scientific officer 50 00:02:34,150 --> 00:02:38,880 at FibroKine, which is a Pittsburgh-based startup 51 00:02:38,880 --> 00:02:43,650 that is developing broad spectrum anti-fibrotic 52 00:02:43,650 --> 00:02:47,630 chemokine peptides to treat organ fibrosis. 53 00:02:47,630 --> 00:02:48,980 So with no further ado, 54 00:02:48,980 --> 00:02:51,343 I will turn it over to Dr. Yates. 55 00:02:57,000 --> 00:02:59,820 - Thank you for that very kind introduction 56 00:02:59,820 --> 00:03:02,163 and the invitation. 57 00:03:03,980 --> 00:03:07,820 I am very excited to present at this festival. 58 00:03:07,820 --> 00:03:10,360 When I began to read a little about it, 59 00:03:10,360 --> 00:03:12,853 I think it's an amazing 60 00:03:14,420 --> 00:03:17,310 festival and efforts that you all are putting together, 61 00:03:17,310 --> 00:03:19,000 you have put together over the years 62 00:03:19,000 --> 00:03:21,053 and I'm happy to be a part this year. 63 00:03:22,300 --> 00:03:23,890 So, 64 00:03:23,890 --> 00:03:27,643 as she mentioned, I have a few, 65 00:03:29,472 --> 00:03:30,910 I guess I can, there we go. 66 00:03:30,910 --> 00:03:35,900 I have a few disclosures that are relevant to this talk. 67 00:03:35,900 --> 00:03:40,140 At the end I will start mention some of the technologies 68 00:03:40,140 --> 00:03:43,440 that we recently developed that are introduced 69 00:03:43,440 --> 00:03:45,240 in the middle of being commercialized, 70 00:03:45,240 --> 00:03:47,403 so I wanna disclose that. 71 00:03:48,990 --> 00:03:53,797 And the overall objective of my talk today 72 00:03:54,680 --> 00:03:57,840 is to really teach you a little bit, 73 00:03:57,840 --> 00:04:01,850 for those who don't know about some of the intrinsic 74 00:04:01,850 --> 00:04:05,000 processes that are involved in tissue repair, 75 00:04:05,000 --> 00:04:09,620 not just in skin but multiple organs. 76 00:04:09,620 --> 00:04:12,830 All organs have the capacity, well most organs I should say, 77 00:04:12,830 --> 00:04:16,810 have the capacity to repair itself. 78 00:04:16,810 --> 00:04:20,840 And I want to kind of walk you through 79 00:04:20,840 --> 00:04:23,640 how we take something at the bench 80 00:04:23,640 --> 00:04:26,400 and start investigating a mechanism, 81 00:04:26,400 --> 00:04:31,400 really the origin of something, our molecular process, 82 00:04:32,060 --> 00:04:35,690 and how we move that forward and translate that 83 00:04:35,690 --> 00:04:38,690 to have impact on patient care 84 00:04:38,690 --> 00:04:40,860 and the development of therapeutics. 85 00:04:40,860 --> 00:04:44,560 So I'll describe the tissue repair process 86 00:04:44,560 --> 00:04:46,040 and the role of chemokines. 87 00:04:46,040 --> 00:04:49,060 I'll tell everyone all about what chemokines are, 88 00:04:49,060 --> 00:04:50,343 for those who don't know. 89 00:04:51,470 --> 00:04:54,642 And we'll talk a little bit about the crosstalk 90 00:04:54,642 --> 00:04:56,837 between cellular functions that happens 91 00:04:56,837 --> 00:05:00,520 during this dynamic process of tissue remodeling. 92 00:05:00,520 --> 00:05:03,840 And I'll describe a translational approach 93 00:05:03,840 --> 00:05:07,710 to the development of therapeutic drugs. 94 00:05:07,710 --> 00:05:10,940 And then I'll summarize the functions 95 00:05:10,940 --> 00:05:13,400 and the cellular dysregulation that leads 96 00:05:13,400 --> 00:05:18,400 to identifying potential targets for treatment. 97 00:05:22,400 --> 00:05:26,120 So if we think about, let me move on here, 98 00:05:27,280 --> 00:05:30,890 when we think about the healing process, right, 99 00:05:30,890 --> 00:05:35,290 healing is a physiological response to trauma. 100 00:05:35,290 --> 00:05:39,717 And that trauma can be very insignificant 101 00:05:41,210 --> 00:05:44,120 where sometimes we don't even know that there is a trauma, 102 00:05:44,120 --> 00:05:46,216 or it can have a major impact 103 00:05:46,216 --> 00:05:49,940 on our different organ systems. 104 00:05:49,940 --> 00:05:53,210 But regardless of that, it usually initiates 105 00:05:53,210 --> 00:05:58,210 a complex pathway of biochemical events and cellular events 106 00:05:58,260 --> 00:06:02,520 that secrete different growth factors and cytokines 107 00:06:02,520 --> 00:06:05,040 in the development of re-establishing the tissue 108 00:06:05,040 --> 00:06:06,870 that was damaged. 109 00:06:06,870 --> 00:06:09,700 And as I mentioned, all tissue, 110 00:06:09,700 --> 00:06:13,740 just about all tissue has the capacity of repairing, 111 00:06:13,740 --> 00:06:15,100 it can be damaged. 112 00:06:15,100 --> 00:06:17,240 And so this is just kind of an overview 113 00:06:17,240 --> 00:06:20,822 to really orient everyone into the impact. 114 00:06:20,822 --> 00:06:25,340 Often I mentioned in talks 115 00:06:25,340 --> 00:06:29,840 that over 45% of deaths 116 00:06:29,840 --> 00:06:33,810 in the U.S. are a result of fibrosis. 117 00:06:33,810 --> 00:06:35,930 And people argued and say, "oh no, 118 00:06:35,930 --> 00:06:40,003 there's cardiovascular disease, there's cancer." 119 00:06:40,003 --> 00:06:42,720 And yes, but ultimately the comorbidity 120 00:06:42,720 --> 00:06:45,750 or the cause of death is organ failure 121 00:06:45,750 --> 00:06:50,750 due to excessive remodeling or fibrotic insult. 122 00:06:51,300 --> 00:06:54,780 And so it is a major issue in itself. 123 00:06:54,780 --> 00:06:57,900 It's a disease but it also contributes, 124 00:06:57,900 --> 00:07:00,490 it also is classified as a comorbidity. 125 00:07:00,490 --> 00:07:03,470 But when we think about uncontrolled healing, 126 00:07:03,470 --> 00:07:05,580 there are three classes 127 00:07:07,010 --> 00:07:10,380 that I want to orient everyone on. 128 00:07:10,380 --> 00:07:12,270 And that's fibrotic wounds, 129 00:07:12,270 --> 00:07:14,580 excessive healing and chronic wounds. 130 00:07:14,580 --> 00:07:16,930 Chronic wounds are these non-healing wounds. 131 00:07:16,930 --> 00:07:21,230 We most are familiar with them in diabetic ulcers, 132 00:07:21,230 --> 00:07:23,570 the venous ulcers or pressure ulcers. 133 00:07:23,570 --> 00:07:27,720 And there are over 6.7 million people 134 00:07:27,720 --> 00:07:31,227 who are suffering from non-healing wounds, chronic wounds. 135 00:07:40,658 --> 00:07:45,350 Okay, then there is tissue injury, right? 136 00:07:45,350 --> 00:07:48,450 So I explained the type of wounds, 137 00:07:48,450 --> 00:07:50,170 but let's talk about the tissue injury. 138 00:07:50,170 --> 00:07:53,720 In my group we focus on 139 00:07:55,000 --> 00:07:56,860 very specific types of injury. 140 00:07:56,860 --> 00:07:57,870 One, as I mentioned, 141 00:07:57,870 --> 00:08:00,743 the chronic wound as we see in a diabetic ulcer. 142 00:08:02,040 --> 00:08:04,040 Also, progressive fibrosis, 143 00:08:04,040 --> 00:08:09,040 this is excessive remodeling of the tissue 144 00:08:10,070 --> 00:08:12,143 due to an autoimmune insult. 145 00:08:13,410 --> 00:08:18,313 Hypertrophic scars, which can be induced by burns. 146 00:08:19,450 --> 00:08:24,450 And lung fibrosis, it can be introduced by autoimmune 147 00:08:25,700 --> 00:08:27,960 or other genetic factors. 148 00:08:27,960 --> 00:08:31,660 Even myocardium fractions after a heart attack, 149 00:08:31,660 --> 00:08:34,950 the myocardium continues to remodel. 150 00:08:34,950 --> 00:08:39,950 And clinicians have done really well at saving folks. 151 00:08:41,064 --> 00:08:43,480 They've made major advances to saving folks 152 00:08:43,480 --> 00:08:44,430 from the heart attack, 153 00:08:44,430 --> 00:08:47,800 but ultimately, the mobility and mortality 154 00:08:47,800 --> 00:08:52,270 comes from the continued remodeling of the heart. 155 00:08:52,270 --> 00:08:57,270 And so our mission is to really dissect 156 00:08:57,670 --> 00:09:01,920 and understand molecular processes that contribute to these 157 00:09:01,920 --> 00:09:04,040 and what are some of their underlying causes, 158 00:09:04,040 --> 00:09:06,410 but also where they overlap. 159 00:09:06,410 --> 00:09:10,260 And look at those processes 160 00:09:10,260 --> 00:09:13,120 and see if we can develop or find targets. 161 00:09:13,120 --> 00:09:15,600 So over the last 15 years, 162 00:09:15,600 --> 00:09:19,040 one of the targets that I have been most interested in 163 00:09:19,040 --> 00:09:20,503 is looking at chemokines. 164 00:09:25,050 --> 00:09:28,870 And so I'll kind of describe the healing process 165 00:09:28,870 --> 00:09:31,393 and then go into what a chemokine is. 166 00:09:35,898 --> 00:09:38,140 I think I'm automatically going, 167 00:09:38,140 --> 00:09:39,550 yeah, there we go. 168 00:09:39,550 --> 00:09:44,550 So the healing process is one that is orchestrated 169 00:09:45,750 --> 00:09:47,470 at the time of insult, 170 00:09:47,470 --> 00:09:51,010 whether it's a insult to the skin 171 00:09:51,010 --> 00:09:52,930 where you have a denuded area, 172 00:09:52,930 --> 00:09:57,490 or if there is a insult or like inflammation 173 00:09:57,490 --> 00:10:02,170 or some type of injury to the underlying tissue 174 00:10:02,170 --> 00:10:06,920 that also initiates the healing process. 175 00:10:06,920 --> 00:10:11,600 And so, when we think about healing, 176 00:10:11,600 --> 00:10:16,040 it's typically classified into three separate phases. 177 00:10:16,040 --> 00:10:19,560 You may hear it's classified in four, 178 00:10:19,560 --> 00:10:21,740 but they are overlapping phases. 179 00:10:21,740 --> 00:10:23,330 But they're not mutually exclusive 180 00:10:23,330 --> 00:10:28,320 in the sense that this dynamic process is going on 181 00:10:29,970 --> 00:10:32,380 almost simultaneously in some parts. 182 00:10:32,380 --> 00:10:37,380 And it mirrors that of what we see in developmental biology, 183 00:10:39,020 --> 00:10:42,893 they are some of the molecular elements of development. 184 00:10:43,730 --> 00:10:46,560 And so hemostasis and inflammation, 185 00:10:46,560 --> 00:10:50,020 it's usually depositing the fibrin matrix 186 00:10:50,020 --> 00:10:51,170 back into the wound. 187 00:10:51,170 --> 00:10:55,390 There are cells that neutrophil and your macrophages 188 00:10:55,390 --> 00:10:56,937 your immune cells that come in 189 00:10:56,937 --> 00:11:00,920 and really help repopulate and restore order. 190 00:11:00,920 --> 00:11:03,800 If it is a open wound, 191 00:11:03,800 --> 00:11:06,870 it helps clear the debris and infection. 192 00:11:06,870 --> 00:11:08,440 If it's a closed wound, 193 00:11:08,440 --> 00:11:13,440 it helps to begin to initiate other cells to enter 194 00:11:13,780 --> 00:11:17,670 into the remodel, the injured area, 195 00:11:17,670 --> 00:11:20,870 but also reduce the inflammation, 196 00:11:20,870 --> 00:11:23,280 remodel, heightening the inflammation, 197 00:11:23,280 --> 00:11:26,803 and then subsequently reducing inflammation. 198 00:11:27,830 --> 00:11:32,520 And so there's also tissue repair or tissue replacement. 199 00:11:32,520 --> 00:11:34,300 This is also sometimes called 200 00:11:34,300 --> 00:11:37,390 the provisional remodeling phase 201 00:11:37,390 --> 00:11:40,910 in which the matrix is then being formed. 202 00:11:40,910 --> 00:11:44,440 And so now you have more of your stromal cells come in, 203 00:11:44,440 --> 00:11:47,110 sector fibroblasts, and your endothelial cells 204 00:11:47,110 --> 00:11:52,110 that want to repopulate or reestablish the integrity 205 00:11:52,360 --> 00:11:53,460 of the tissue. 206 00:11:53,460 --> 00:11:55,802 But if the tissue was damaged in such a way 207 00:11:55,802 --> 00:11:58,010 that now the matrix and connective tissue 208 00:11:58,010 --> 00:12:01,610 are no longer functional for the particular organ, 209 00:12:01,610 --> 00:12:04,720 the fibroblast, the endothelial cells play a major role 210 00:12:04,720 --> 00:12:09,720 in coming in to help repopulate and restore order. 211 00:12:11,240 --> 00:12:16,240 And so this is at the same point in which we began to see 212 00:12:16,400 --> 00:12:18,803 a decrease in normal healing. 213 00:12:19,710 --> 00:12:21,610 A decrease in inflammation, 214 00:12:21,610 --> 00:12:24,150 so the inflammation begins to resolve. 215 00:12:24,150 --> 00:12:28,140 And then last, there is a contraction or remodeling 216 00:12:28,140 --> 00:12:30,230 where everything is reorganized 217 00:12:30,230 --> 00:12:33,040 and there's a realignment of the tissue. 218 00:12:33,040 --> 00:12:36,500 So ultimately there's minimal scar. 219 00:12:36,500 --> 00:12:41,500 After birth, there is the all scar from all injury, 220 00:12:41,630 --> 00:12:44,180 there's really no scarless injury. 221 00:12:44,180 --> 00:12:49,160 We do see scarless injury in fetal tissue, 222 00:12:49,160 --> 00:12:53,673 which gives us some insight into how development 223 00:12:55,539 --> 00:12:58,670 could play a role, understanding how development 224 00:12:58,670 --> 00:13:02,870 can play a role in helping us reduce scar as we age. 225 00:13:02,870 --> 00:13:07,760 But at this point, there will be a minimal scar 226 00:13:07,760 --> 00:13:10,710 after injury during normal healing. 227 00:13:10,710 --> 00:13:14,270 But what is the pathological state and have most concerned 228 00:13:14,270 --> 00:13:18,720 is when there is excessive or there's a failure to heal. 229 00:13:18,720 --> 00:13:22,513 And we like to classify this as a failure to start, 230 00:13:23,380 --> 00:13:27,150 which is the chronic wounds, and then a failure to stop, 231 00:13:27,150 --> 00:13:30,053 which is also considered excessive healing. 232 00:13:34,629 --> 00:13:37,460 So if I can just briefly walk you through 233 00:13:39,470 --> 00:13:44,413 some of the general elements of this is, 234 00:13:45,950 --> 00:13:48,340 if you look at the fingertip there 235 00:13:48,340 --> 00:13:51,410 everyone has had some type of minor injury, 236 00:13:51,410 --> 00:13:54,680 we call it a superficial injury, 237 00:13:54,680 --> 00:13:58,930 and this is just a nice dramatic image 238 00:13:58,930 --> 00:14:00,910 to kind of get everyone on the same page. 239 00:14:00,910 --> 00:14:03,536 But you have the bleeding, it clots. 240 00:14:03,536 --> 00:14:06,640 Then there's the scab, 241 00:14:06,640 --> 00:14:08,920 and this is where there's that interplay 242 00:14:08,920 --> 00:14:11,363 between the fibroblast and the macrophages, 243 00:14:11,363 --> 00:14:15,180 they're trying to restore homeostasis 244 00:14:15,180 --> 00:14:19,090 by increasing the inflammation, but also getting rid 245 00:14:19,090 --> 00:14:23,705 of all of the debris and any passages that may have entered. 246 00:14:23,705 --> 00:14:27,310 And then, we move into the proliferative phase 247 00:14:27,310 --> 00:14:30,883 where the fibroblast need to repopulate that tissue. 248 00:14:33,240 --> 00:14:36,770 Sorry, I'm trying to move my, there we go. 249 00:14:36,770 --> 00:14:39,890 We need to repopulate that the tissue. 250 00:14:39,890 --> 00:14:44,730 And then there's a nice layer that is covering 251 00:14:44,730 --> 00:14:48,840 or that will restore at least the outer layer, 252 00:14:48,840 --> 00:14:52,330 the one that we can grossly see will be healed. 253 00:14:52,330 --> 00:14:55,890 And if everything goes well, the underlying tissue 254 00:14:55,890 --> 00:14:58,793 which we consider the dermis will be healed as well. 255 00:15:02,220 --> 00:15:05,550 But in chronic wounds, this doesn't go that way. 256 00:15:05,550 --> 00:15:09,820 There is a persistence of healing. 257 00:15:09,820 --> 00:15:14,820 And in fact, it's really stalled in between the inflammation 258 00:15:15,700 --> 00:15:19,780 and proliferative phases in our remodeling phase. 259 00:15:19,780 --> 00:15:23,350 And in some cases, chronic ones can be so severe 260 00:15:23,350 --> 00:15:27,320 that patients are seen in the clinic multiple times a week 261 00:15:27,320 --> 00:15:31,955 for years to constantly be debriefed and to remove 262 00:15:31,955 --> 00:15:36,955 the dead tissue in which this wound is failing to heal. 263 00:15:44,530 --> 00:15:47,490 And then there's the excessive wounds. 264 00:15:47,490 --> 00:15:51,610 And it's also could be progressive. 265 00:15:51,610 --> 00:15:54,720 What I'm showing you here is, oops! 266 00:15:54,720 --> 00:15:55,553 That's a... 267 00:15:57,170 --> 00:15:58,110 That should have been removed. 268 00:15:58,110 --> 00:16:03,110 But I'm showing you here is a liver fibrosis 269 00:16:03,730 --> 00:16:08,320 in which the liver has a insult, 270 00:16:08,320 --> 00:16:10,770 in this case it's fatty liver. 271 00:16:10,770 --> 00:16:13,630 And or it could be a viral infection, 272 00:16:13,630 --> 00:16:18,480 and initiates the fibrosis and then the liver begins scar. 273 00:16:18,480 --> 00:16:22,320 Now the liver happens to be extremely regenerative organ, 274 00:16:22,320 --> 00:16:27,320 and it turns over constantly, but in some cases 275 00:16:27,730 --> 00:16:32,120 such as fatty liver that is caused 276 00:16:33,030 --> 00:16:38,030 through multiple insults, the fibrosis outweigh, 277 00:16:38,820 --> 00:16:41,933 doesn't allow for appropriate regeneration. 278 00:16:42,810 --> 00:16:47,089 So, just to kinda tell you, like, 279 00:16:47,089 --> 00:16:52,089 I kind of give really basic science and general overview 280 00:16:52,630 --> 00:16:56,000 of the healing process, but it's not that simple. 281 00:16:56,000 --> 00:17:01,000 And this is sort of a play, one of the first in my lab, 282 00:17:02,260 --> 00:17:05,060 did this really nice diagram. 283 00:17:05,060 --> 00:17:07,760 Well, when we were thinking about how "The Game of Thrones" 284 00:17:07,760 --> 00:17:10,230 kind of, really what's going on 285 00:17:10,230 --> 00:17:13,390 and how the interplay between the fibroblasts 286 00:17:13,390 --> 00:17:16,660 and the macrophages and other cell types, 287 00:17:16,660 --> 00:17:19,630 also the molecules, the secreted factors 288 00:17:19,630 --> 00:17:21,020 that they are secreting. 289 00:17:21,020 --> 00:17:24,080 All of this is going on and it's such a dynamic process, 290 00:17:24,080 --> 00:17:29,080 it's really who wins is gonna really determine the fate 291 00:17:29,340 --> 00:17:32,060 of the overall healing. 292 00:17:32,060 --> 00:17:37,060 And what we have recently seen is that who wins 293 00:17:37,510 --> 00:17:42,510 is or who outsmarts the other cell type, 294 00:17:43,050 --> 00:17:48,050 or what cell type dominate really does dictate 295 00:17:49,970 --> 00:17:53,280 the underlying pathology of the wound 296 00:17:53,280 --> 00:17:56,463 and ultimately the long-term trajectory. 297 00:17:58,690 --> 00:18:02,680 So what I'm describing to you is the process 298 00:18:02,680 --> 00:18:04,330 that has been well-described. 299 00:18:04,330 --> 00:18:08,670 It was initially described by a well-known scientist, 300 00:18:08,670 --> 00:18:13,282 Nina Disel, and her focus was really on oncology . 301 00:18:13,282 --> 00:18:16,200 and in cancer biology. 302 00:18:16,200 --> 00:18:18,803 But it's called dynamic reciprocity. 303 00:18:19,660 --> 00:18:22,840 And dynamic reciprocity is really the origin 304 00:18:22,840 --> 00:18:25,140 of how behavior changes. 305 00:18:25,140 --> 00:18:29,540 And what it describes is that there's this interplay 306 00:18:29,540 --> 00:18:34,540 between all facets of the tissue from the single molecule, 307 00:18:36,940 --> 00:18:40,530 the structure of the tissue, 308 00:18:40,530 --> 00:18:41,800 the cells, 309 00:18:41,800 --> 00:18:46,240 the secreted factors, all of these things actually interplay 310 00:18:46,240 --> 00:18:51,240 with each other to directly dictate the behavior. 311 00:18:52,430 --> 00:18:57,430 And this type of cell cell, cell matrix molecule, 312 00:18:57,890 --> 00:19:02,400 cell autocrine, paracrine signaling 313 00:19:02,400 --> 00:19:05,300 is what makes the tissue repair process. 314 00:19:05,300 --> 00:19:09,430 It's freely dynamic, but it's also been a major challenge 315 00:19:09,430 --> 00:19:14,003 for scientists to understand what element to actually treat. 316 00:19:14,900 --> 00:19:18,320 And so what I have been interested in 317 00:19:18,320 --> 00:19:22,160 is looking at chemokines, the role of chemokines. 318 00:19:22,160 --> 00:19:23,310 So what are chemokines? 319 00:19:24,620 --> 00:19:28,220 Chemokines are small cytokines, 320 00:19:28,220 --> 00:19:31,640 and they are extremely versatile, 321 00:19:31,640 --> 00:19:35,260 most have multiple functions. 322 00:19:35,260 --> 00:19:37,300 Some are very ubiquitous in nature 323 00:19:37,300 --> 00:19:41,490 in which they can be expressed in multiple cell types, 324 00:19:41,490 --> 00:19:46,490 but function either in parallel, but also in opposition. 325 00:19:48,790 --> 00:19:51,950 And which I will describe to you a bit. 326 00:19:51,950 --> 00:19:56,240 But when we look at that, this is kind of a broad element, 327 00:19:56,240 --> 00:19:59,010 but when we look at the involvement of chemokines 328 00:19:59,010 --> 00:20:02,098 in cellular and biological processes, 329 00:20:02,098 --> 00:20:07,098 it covers a very wide net from cell differentiation, 330 00:20:10,299 --> 00:20:15,299 endocytosis, immune cell development to respiratory burst, 331 00:20:18,390 --> 00:20:21,460 structure and function of the cells, 332 00:20:21,460 --> 00:20:25,670 apoptosis, and then even cell movement. 333 00:20:25,670 --> 00:20:29,110 Originally, if you know, when I first started in this 334 00:20:29,110 --> 00:20:31,290 chemokine first sort of new on the scene 335 00:20:31,290 --> 00:20:35,730 and they were all thought to be major players 336 00:20:35,730 --> 00:20:39,620 and immune or inflammation regulated processes. 337 00:20:39,620 --> 00:20:43,280 What we now know is that they play a much broader role. 338 00:20:43,280 --> 00:20:48,280 Yes, they are key in initiating or continuing 339 00:20:51,970 --> 00:20:56,500 the chemotactic insult or allowing cells to come 340 00:20:56,500 --> 00:21:00,050 or even halt into the injured area. 341 00:21:00,050 --> 00:21:04,220 But equally, they play a role in modulating 342 00:21:04,220 --> 00:21:07,330 how our stromal cells, like our fibroblast 343 00:21:07,330 --> 00:21:09,990 produce the matrix to develop, 344 00:21:09,990 --> 00:21:14,330 and the connective tissue to restore the integrity 345 00:21:14,330 --> 00:21:15,263 of the tissue. 346 00:21:16,100 --> 00:21:21,100 And so we have really focused our work over the last 347 00:21:23,220 --> 00:21:27,120 10 to 15 years on trying to understand 348 00:21:27,120 --> 00:21:31,450 how they can simultaneously modulate inflammation, 349 00:21:31,450 --> 00:21:36,450 but also matrix for modeling in the setting 350 00:21:36,560 --> 00:21:38,123 of a injured tissue. 351 00:21:41,870 --> 00:21:44,780 And so this is just to show that chemokines 352 00:21:44,780 --> 00:21:48,303 are widely known to be biomarkers, 353 00:21:49,240 --> 00:21:54,240 and noted to be dysregulated in a host of diseases, 354 00:21:55,720 --> 00:21:57,200 so this is just kind of give you an overview 355 00:21:57,200 --> 00:22:02,200 of the different organ systems in which they are involved. 356 00:22:03,720 --> 00:22:08,560 I've highlighted the ones that we're gonna discuss today. 357 00:22:08,560 --> 00:22:11,820 And those are of excessive healing, 358 00:22:11,820 --> 00:22:14,370 constitutes what we see in myocardial infractions 359 00:22:14,370 --> 00:22:19,370 scleroderma, IPS, and also fatty liver disease. 360 00:22:22,240 --> 00:22:25,410 So going back to the overview process 361 00:22:25,410 --> 00:22:29,670 that I mentioned earlier in which inflammation 362 00:22:29,670 --> 00:22:32,950 is the initial stage and there's a recruitment itself, 363 00:22:32,950 --> 00:22:35,250 this is where chemokines come in. 364 00:22:35,250 --> 00:22:38,960 And they actually play a role in allowing the platelets 365 00:22:38,960 --> 00:22:42,220 to release neutrophils to release and be recruited. 366 00:22:42,220 --> 00:22:44,703 And they are, 367 00:22:46,650 --> 00:22:48,290 simultaneously at this stage, 368 00:22:48,290 --> 00:22:52,173 promoting the persistence of angiogenesis. 369 00:23:00,490 --> 00:23:03,550 Their involvement in the proliferative phase 370 00:23:04,680 --> 00:23:08,114 stretches from the neovascular support 371 00:23:08,114 --> 00:23:13,110 of cellular proliferation and migration, 372 00:23:13,110 --> 00:23:16,680 also involved in the 373 00:23:18,120 --> 00:23:22,050 re-epithelization of the epidermal layer 374 00:23:22,050 --> 00:23:24,403 is which we see in skin. 375 00:23:25,380 --> 00:23:30,380 They really help, aid and stimulate macrophages 376 00:23:30,910 --> 00:23:35,910 to polarize and enter into a different phenotype 377 00:23:37,070 --> 00:23:40,220 in which TGF beta are released to become 378 00:23:40,220 --> 00:23:44,620 until they're in a more pro-fibrotic profile. 379 00:23:44,620 --> 00:23:48,850 And they also are play a major role 380 00:23:48,850 --> 00:23:53,400 in the initiation of 381 00:23:53,400 --> 00:23:56,020 what we consider fibroblasts, 382 00:23:56,020 --> 00:23:58,480 differentiation into myofibroblasts, 383 00:23:58,480 --> 00:24:01,520 which are these more contractile 384 00:24:01,520 --> 00:24:06,023 or fibrotic fibroblasts type of classification. 385 00:24:09,130 --> 00:24:13,040 And so when there's this imbalance or disagree, 386 00:24:13,040 --> 00:24:15,200 there really is this sort of battle 387 00:24:16,060 --> 00:24:19,970 between the roles that the chemokines are playing 388 00:24:19,970 --> 00:24:24,910 and how they will interact with the different cell types. 389 00:24:24,910 --> 00:24:28,360 Because the same chemokine and their receptors 390 00:24:28,360 --> 00:24:33,270 are expressed widely on multiple cell types. 391 00:24:33,270 --> 00:24:37,910 And they're secreted equally by multiple cell types 392 00:24:37,910 --> 00:24:40,418 in the wound setting. 393 00:24:40,418 --> 00:24:45,193 And this does cause, it oftentimes, this imbalance 394 00:24:47,080 --> 00:24:49,600 and this imbalance is what we see 395 00:24:49,600 --> 00:24:53,640 that develops the pathological state of fibrosis. 396 00:24:53,640 --> 00:24:57,780 And then the case that I'm gonna describe today 397 00:24:57,780 --> 00:25:01,310 in skin fibrosis, what we see is that the imbalance 398 00:25:01,310 --> 00:25:04,300 and these metallic proteases, 399 00:25:04,300 --> 00:25:08,010 which are these tissue 400 00:25:10,117 --> 00:25:12,650 degradation proteins 401 00:25:12,650 --> 00:25:17,650 that we see in their inhibitors when it causes that 402 00:25:18,040 --> 00:25:21,740 there's like a stoichiometric imbalance, 403 00:25:21,740 --> 00:25:24,590 there isn't that is lost. 404 00:25:24,590 --> 00:25:28,260 This is when we see a persistence in tissue remodeling, 405 00:25:28,260 --> 00:25:30,980 that ultimately ends in fibrosis. 406 00:25:30,980 --> 00:25:35,980 And if that fibrotic state, if that imbalance is unchecked, 407 00:25:36,160 --> 00:25:40,103 then the organ ultimately fails. 408 00:25:50,242 --> 00:25:55,242 There's a potential case to be made 409 00:25:57,370 --> 00:25:59,640 that because they're so widely expressed 410 00:25:59,640 --> 00:26:01,960 and they're so ubiquitous, that the chemokines 411 00:26:01,960 --> 00:26:05,900 could potentially be a target for in treatment. 412 00:26:05,900 --> 00:26:08,070 And so for the rest of the talk, 413 00:26:08,070 --> 00:26:11,500 I am gonna try to make that case to you 414 00:26:11,500 --> 00:26:16,410 by focusing in on two cell types that are of most interest 415 00:26:16,410 --> 00:26:19,830 to us and that are key players in the healing process. 416 00:26:19,830 --> 00:26:24,253 And that's the macrophage and the fibroblast. 417 00:26:25,200 --> 00:26:28,680 So, as I mentioned, macrophages are these immune cells, 418 00:26:28,680 --> 00:26:32,433 they're extremely versatile by phagocytose. 419 00:26:33,550 --> 00:26:37,030 They play a major role in inflammation 420 00:26:37,030 --> 00:26:40,290 but also helping restore homeostasis. 421 00:26:40,290 --> 00:26:44,253 They can polarize, and, 422 00:26:45,350 --> 00:26:47,440 I won't get into 423 00:26:50,009 --> 00:26:53,730 the deep immunology of the classifications 424 00:26:53,730 --> 00:26:55,490 of their levels of polarizing, 425 00:26:55,490 --> 00:27:00,490 but we do know that these cells polarize on a spectrum level 426 00:27:00,961 --> 00:27:05,961 and into a different phenotype in which they can go 427 00:27:06,820 --> 00:27:11,820 from being really pro-inflammatory to anti-fibrotic. 428 00:27:12,580 --> 00:27:16,523 So these are very dynamic cells. 429 00:27:17,490 --> 00:27:22,490 On the other hand, there are the stromal cells 430 00:27:22,780 --> 00:27:26,010 that I mentioned or the fibroblast equally, 431 00:27:26,010 --> 00:27:29,140 very versatile cells, they can differentiate 432 00:27:29,140 --> 00:27:32,390 and become proliferative, and if they migrate 433 00:27:32,390 --> 00:27:34,950 and then they go into this reactive state. 434 00:27:34,950 --> 00:27:39,043 What you're seeing here is a uniphasic image 435 00:27:40,480 --> 00:27:44,610 of fibroblast in their reactive state 436 00:27:44,610 --> 00:27:48,890 where they are expressing transcription factor, 437 00:27:48,890 --> 00:27:52,190 alpha-smooth muscle actin, and we can see 438 00:27:52,190 --> 00:27:53,610 that they're becoming contractile, 439 00:27:53,610 --> 00:27:56,390 and this is when they will start synthesizing 440 00:27:56,390 --> 00:28:01,390 the matrix that is needed to repopulate the injured area 441 00:28:03,770 --> 00:28:05,470 or remodel the injury area. 442 00:28:08,200 --> 00:28:13,200 So, macrophages and fibroblasts are tissue resident cells 443 00:28:14,040 --> 00:28:15,240 in the skin. 444 00:28:15,240 --> 00:28:18,010 And so they're going from, well, 445 00:28:18,010 --> 00:28:20,360 the fibroblast are going from a quiescent state 446 00:28:21,480 --> 00:28:25,280 to this reactive state, which we consider 447 00:28:25,280 --> 00:28:28,410 active fibroblasts, or even in some cases 448 00:28:28,410 --> 00:28:30,183 can be a fibrotic fibroblast. 449 00:28:31,490 --> 00:28:35,590 And in which case they're matrix producing function 450 00:28:35,590 --> 00:28:40,590 is tightened, and they begin to secrete matrikines 451 00:28:40,900 --> 00:28:45,900 such as tenascin and laminin and collagen. 452 00:28:46,180 --> 00:28:49,390 And in the manner in which they secrete them, 453 00:28:49,390 --> 00:28:53,120 it really dictates the overall mechanical properties 454 00:28:53,120 --> 00:28:57,793 of the wound bed, and also the integrity of the wound. 455 00:29:00,520 --> 00:29:04,600 Here, where I'm showing you is CXCR3, 456 00:29:04,600 --> 00:29:08,460 which is a chemokine receptor to CXCL10. 457 00:29:08,460 --> 00:29:12,853 And earlier we have shown, and others have shown 458 00:29:12,853 --> 00:29:17,853 that CXCL10 is a stop signal for these fibroblasts, 459 00:29:18,780 --> 00:29:22,800 it shuts off the matrix-producing function 460 00:29:22,800 --> 00:29:23,980 of the fibroblasts. 461 00:29:23,980 --> 00:29:26,610 It inhibits their motility. 462 00:29:26,610 --> 00:29:30,570 It even blocks the motility, well known 463 00:29:33,930 --> 00:29:35,790 motility inducer, 464 00:29:35,790 --> 00:29:40,773 and fibrotic initiator of TGF beta. 465 00:29:45,790 --> 00:29:49,900 On the other hand, these macrophages 466 00:29:51,780 --> 00:29:56,160 which we, these initial macrophages, 467 00:29:56,160 --> 00:29:58,410 they're also tissue resident cells, 468 00:29:58,410 --> 00:30:00,308 but when they become very, 469 00:30:00,308 --> 00:30:05,308 have this heightened inflammatory phenotype, 470 00:30:05,400 --> 00:30:10,090 they're classified as M1 macrophages, 471 00:30:10,090 --> 00:30:14,680 and they actually secrete and express 472 00:30:15,680 --> 00:30:20,680 CXCR3 but also secrete high levels of CXCL10. 473 00:30:21,070 --> 00:30:23,800 They at this stage, they're extremely migratory 474 00:30:23,800 --> 00:30:27,420 and proliferative, but yet when they switch back 475 00:30:27,420 --> 00:30:32,340 to more the resolving phage, which we classify as M2, 476 00:30:32,340 --> 00:30:37,340 the expression and the secretion of CXCL10 is lost. 477 00:30:37,400 --> 00:30:42,400 And so what I'm trying to convey to everyone 478 00:30:42,500 --> 00:30:47,500 is that there's this yin-yang, this imbalance, 479 00:30:49,090 --> 00:30:53,410 the fibroblast in CXCL10 will stop 480 00:30:53,410 --> 00:30:57,260 and halt it's initiation and progression 481 00:30:57,260 --> 00:31:01,830 of continuing to induce this fibrotic state into the tissue. 482 00:31:01,830 --> 00:31:06,060 But on the other hand, in the macrophages 483 00:31:06,060 --> 00:31:07,740 it's promoting motility, 484 00:31:07,740 --> 00:31:11,310 it's promoting increased inflammation 485 00:31:11,310 --> 00:31:16,310 or sustained inflammation through multiple pathways. 486 00:31:16,420 --> 00:31:19,087 It is interfering gamma induced, 487 00:31:19,087 --> 00:31:21,460 and this is what we're kind of showing here. 488 00:31:21,460 --> 00:31:22,780 And so it does go through 489 00:31:25,888 --> 00:31:28,790 the cascade of events, 490 00:31:28,790 --> 00:31:32,050 and so we see it's full in compliment, 491 00:31:32,050 --> 00:31:37,050 we see it's role in innate as well as adaptive view. 492 00:31:40,287 --> 00:31:45,287 So we think that the life of macrophages and fibroblast, 493 00:31:45,950 --> 00:31:50,010 although widely considered to date 494 00:31:50,010 --> 00:31:54,250 as two separate class of cells, have more in common 495 00:31:55,210 --> 00:32:00,210 than we in the community have initially realized. 496 00:32:01,490 --> 00:32:04,510 And in fact, they work in concert with each other, 497 00:32:04,510 --> 00:32:06,313 they're sort of silent partners. 498 00:32:07,550 --> 00:32:09,420 And so there were a couple of questions 499 00:32:09,420 --> 00:32:13,190 that we've been asking, is like really what instructs 500 00:32:13,190 --> 00:32:18,190 the fibroblasts to adapt a pro-inflammatory phenotype? 501 00:32:18,550 --> 00:32:21,870 So these fibroblasts can, as I mentioned, 502 00:32:21,870 --> 00:32:25,100 when they're secreting these chemokine, 503 00:32:25,100 --> 00:32:28,810 we have profiles that we've done in genomic 504 00:32:28,810 --> 00:32:32,420 and proteomic profiling, and found that they really do have 505 00:32:32,420 --> 00:32:35,900 a pro-inflammatory signature at different stages 506 00:32:35,900 --> 00:32:37,160 in the healing. 507 00:32:37,160 --> 00:32:40,060 They could be pro-wounding and they could be pro-fibrotic. 508 00:32:41,360 --> 00:32:45,330 But then also, they can, 509 00:32:45,330 --> 00:32:48,090 especially when they're highly expressing 510 00:32:48,090 --> 00:32:51,310 the CXCL10 chemokine, 511 00:32:51,310 --> 00:32:53,490 they can reveal 512 00:32:53,490 --> 00:32:58,323 a more anti-inflammatory, anti-fibrotic 513 00:32:58,323 --> 00:33:01,530 and pro-resolving profile. 514 00:33:01,530 --> 00:33:06,530 So how is this possible and what is the appropriate balance 515 00:33:08,340 --> 00:33:13,340 or what are the modulators of keeping this imbalance 516 00:33:15,120 --> 00:33:18,820 in play to allow the pathology 517 00:33:18,820 --> 00:33:22,643 or the pathological state of fibrosis to continue? 518 00:33:27,087 --> 00:33:29,310 Or the other question is, 519 00:33:29,310 --> 00:33:33,160 what is the environmental influences 520 00:33:33,160 --> 00:33:35,630 that contribute to that? 521 00:33:35,630 --> 00:33:40,630 And so we have postulated that there really is this cyclic 522 00:33:43,820 --> 00:33:48,820 element to healing that involves this back and forth 523 00:33:49,860 --> 00:33:54,860 between macrophages and fibroblasts in a fibrotic state. 524 00:33:55,260 --> 00:34:00,240 And in each case, the activated fibroblast can also 525 00:34:00,240 --> 00:34:05,240 perpetuate the inflammation by being pro-fibrotic. 526 00:34:07,221 --> 00:34:10,420 And in the macrophage, on the other hand, 527 00:34:10,420 --> 00:34:13,030 can continue or 528 00:34:14,400 --> 00:34:16,580 sustain the pro-fibrotic state 529 00:34:16,580 --> 00:34:18,363 by being pro-inflammatory. 530 00:34:23,320 --> 00:34:27,600 So I'll walk you through just one, 531 00:34:27,600 --> 00:34:30,810 experimental system that we've used 532 00:34:30,810 --> 00:34:33,837 at the bench in which, we wanted to, 533 00:34:33,837 --> 00:34:38,640 kind of test our hypothesis about the interplay 534 00:34:38,640 --> 00:34:40,580 between fibroblasts and macrophages. 535 00:34:40,580 --> 00:34:45,190 We really wanted to look at, their autocrine signaling 536 00:34:45,190 --> 00:34:48,130 as well as the pair Quinn signaling 537 00:34:48,130 --> 00:34:52,200 between the two in the Jackson green signaling. 538 00:34:52,200 --> 00:34:53,640 And so in this next one 539 00:34:53,640 --> 00:34:57,713 we've taken both narrow derived monocytes. 540 00:34:58,670 --> 00:35:02,570 They have been polarized with appropriate simulators 541 00:35:02,570 --> 00:35:07,570 to reveal the phenotype of a monocyte or a M1, 542 00:35:09,400 --> 00:35:10,853 or M2 macrophage. 543 00:35:11,930 --> 00:35:15,100 We've taken skin fibroblasts as well. 544 00:35:15,100 --> 00:35:17,400 And we've either induced them 545 00:35:17,400 --> 00:35:21,380 with a pro-inflammatory factor TNF alpha 546 00:35:21,380 --> 00:35:25,713 or a pro-fibrotic factors, I mentioned before to TGF beta. 547 00:35:31,330 --> 00:35:34,903 And the downstream analysis that I'll kind of go through, 548 00:35:35,900 --> 00:35:38,770 if we've done functional analysis on those protein profiling 549 00:35:38,770 --> 00:35:40,593 and transcriptional profiling. 550 00:35:45,120 --> 00:35:49,270 But to give you overview we look transcriptionally 551 00:35:49,270 --> 00:35:53,298 and we wanted to characterize the secretome 552 00:35:53,298 --> 00:35:56,430 and matrisome of these cells 553 00:35:56,430 --> 00:35:59,620 due to the crosstalk when these cells are cultured together 554 00:36:02,467 --> 00:36:03,540 in a Transwell. 555 00:36:03,540 --> 00:36:05,780 So there's this, this pair Krantz signaling 556 00:36:05,780 --> 00:36:07,570 that we were trying to identify. 557 00:36:07,570 --> 00:36:11,500 We were able to see that the macrophages differentially 558 00:36:12,820 --> 00:36:16,160 alter the fibroblast secretome. 559 00:36:16,160 --> 00:36:19,682 And so the fibroblast had this, 560 00:36:19,682 --> 00:36:24,350 anti inflammatory secretome, 561 00:36:24,350 --> 00:36:28,690 and when they were induced 562 00:36:28,690 --> 00:36:33,690 or co stimulated with, in one macrophages 563 00:36:33,930 --> 00:36:37,890 we see increase in TNF alpha, pro-inflammatory cytokine 564 00:36:39,430 --> 00:36:40,943 with the increase in TNF 565 00:36:45,570 --> 00:36:48,110 interfering gamma CXL10 566 00:36:48,110 --> 00:36:49,700 and IO1 beta. 567 00:36:49,700 --> 00:36:54,700 So this pro-inflammatory profile is conceived. 568 00:36:57,460 --> 00:37:00,040 And then the macrophages also difference 569 00:37:00,950 --> 00:37:03,090 is for us the matrix tone, right? 570 00:37:03,090 --> 00:37:04,910 So now we're looking at the matrix 571 00:37:05,964 --> 00:37:10,887 and the M1 interestingly, while we see there, 572 00:37:12,890 --> 00:37:14,980 the causal effects of them, 573 00:37:14,980 --> 00:37:18,310 inducing a pro-inflammatory product profile 574 00:37:18,310 --> 00:37:23,310 in the fibroblasts, it had a anti-fibrotic effect. 575 00:37:24,180 --> 00:37:28,260 So what we're showing here is decline, 576 00:37:28,260 --> 00:37:33,260 which is a anti-fibrotic matrikine or matrix protein, 577 00:37:34,410 --> 00:37:39,410 and that's increased where pro-fibrotic matrikines 578 00:37:39,410 --> 00:37:43,693 such as collagen, one and two, matrixyl 579 00:37:44,890 --> 00:37:49,303 are increased with the addition of M2. 580 00:37:51,400 --> 00:37:53,223 So what does that tell us, right? 581 00:37:54,560 --> 00:37:58,240 That the relationship is complicated one, 582 00:37:58,240 --> 00:38:03,240 but also that, if we think about this in the context of 583 00:38:04,078 --> 00:38:09,078 the tissue remodeling and the pathological state remodeling, 584 00:38:12,370 --> 00:38:17,090 they are actually, the theory or 585 00:38:17,090 --> 00:38:21,120 the concept of dynamic reciprocity is at play here. 586 00:38:21,120 --> 00:38:25,710 And that is where the, one cell type 587 00:38:25,710 --> 00:38:29,640 is actually initiating an alternate phenotype, 588 00:38:29,640 --> 00:38:33,050 which is unfavorable in this case and the other 589 00:38:33,050 --> 00:38:36,260 and is perpetuating a cyclic event. 590 00:38:36,260 --> 00:38:39,530 And it prevents the overall resolution 591 00:38:39,530 --> 00:38:41,753 or resolving of the tissue. 592 00:38:46,440 --> 00:38:51,440 And so we've even gone back and, taken those data and, 593 00:38:52,590 --> 00:38:54,010 things that we've seen at the bench 594 00:38:54,010 --> 00:38:56,360 and tried to see if we can change this 595 00:38:56,360 --> 00:38:57,650 in the initial settings 596 00:38:57,650 --> 00:39:01,050 we can actually alter or change the trajectory 597 00:39:01,050 --> 00:39:05,540 by inducing a specific phenotype of macrophages 598 00:39:05,540 --> 00:39:09,490 into the wound bed, during the healing response. 599 00:39:09,490 --> 00:39:11,480 And so that's what we did here. 600 00:39:11,480 --> 00:39:12,663 We induced, 601 00:39:14,810 --> 00:39:18,180 we created an injury in the animal 602 00:39:18,180 --> 00:39:21,630 and we either added M1 or M2 fibroblast, 603 00:39:22,975 --> 00:39:26,230 M1 or M2 macrophages with the fibroblasts. 604 00:39:26,230 --> 00:39:28,490 So this was what we consider a cell therapy 605 00:39:28,490 --> 00:39:30,670 or a transplant in there. 606 00:39:30,670 --> 00:39:35,670 And so the overarching conclusion that I want you to 607 00:39:36,450 --> 00:39:40,470 kind of see here, is that with the M2 608 00:39:40,470 --> 00:39:43,070 as I mentioned previously, what we saw in our 609 00:39:43,070 --> 00:39:47,000 in these studies is that it introduced 610 00:39:47,000 --> 00:39:52,000 this pro-fibrotic fibroblast phenotype 611 00:39:54,080 --> 00:39:59,080 and the M1s are less, had it more of an anti-fibrotic. 612 00:39:59,730 --> 00:40:01,840 And so what I'm showing you 613 00:40:01,840 --> 00:40:05,220 on the bottom panel is 30 days post healing 614 00:40:05,220 --> 00:40:08,170 where we can really evaluate the alignment 615 00:40:08,170 --> 00:40:10,810 and the integrity of the tissue. 616 00:40:10,810 --> 00:40:14,040 And so this is a picrosirius red staining. 617 00:40:14,040 --> 00:40:17,900 And what we do is we image these 618 00:40:17,900 --> 00:40:22,620 under bio forensic polarized light to really assess 619 00:40:22,620 --> 00:40:25,660 the collagen content or the collagen types. 620 00:40:25,660 --> 00:40:28,893 We can differentiate between collagen one and three, 621 00:40:29,770 --> 00:40:32,290 mature and immature collagens. 622 00:40:32,290 --> 00:40:34,990 But also look at the alignment of the tissue 623 00:40:34,990 --> 00:40:37,170 which really gives us some close 624 00:40:37,170 --> 00:40:40,360 or understanding our assessment 625 00:40:40,360 --> 00:40:45,360 of the overall fibrotic state of the of the organ. 626 00:40:47,480 --> 00:40:51,770 And what we see is that with M1 as expected, 627 00:40:51,770 --> 00:40:54,372 where there's anti, we see increase in decrinal 628 00:40:54,372 --> 00:40:59,372 or anti fibrotic molecules, the alignment is more in order 629 00:41:00,860 --> 00:41:03,470 of what we consider organized. 630 00:41:03,470 --> 00:41:08,420 And with the M2, we see higher levels of collagen one 631 00:41:08,420 --> 00:41:11,330 wanting to lessen and fibronectin 632 00:41:11,330 --> 00:41:16,330 and we see this bright red which signifies disalignment 633 00:41:18,060 --> 00:41:21,010 and a thickening of the tissue 634 00:41:21,010 --> 00:41:23,413 but also just organization. 635 00:41:29,250 --> 00:41:33,490 And so this can be quantified in multiple ways 636 00:41:33,490 --> 00:41:37,570 but we use frontera transfers to quantify this, 637 00:41:37,570 --> 00:41:42,570 to confirm that there is a long-term effect of these outcome 638 00:41:43,890 --> 00:41:48,010 to altering the wound trajectory by failure to transplant. 639 00:41:48,010 --> 00:41:53,010 So we can change the trajectory of a potential wound 640 00:41:54,120 --> 00:41:57,613 by introducing specific cell phenotypes. 641 00:42:03,260 --> 00:42:06,360 So since we are able to do that, I wanted to step back again 642 00:42:06,360 --> 00:42:10,790 and look at how the chemokine of interests 643 00:42:11,690 --> 00:42:15,700 and that we see in both macrophages and the fibroblast 644 00:42:15,700 --> 00:42:20,410 that are functioning in a ubiquitous nature, plays a role. 645 00:42:20,410 --> 00:42:25,180 And so we did similar studies using the CXCR3 646 00:42:25,180 --> 00:42:27,507 which is the receptor for CXCR10, 647 00:42:29,040 --> 00:42:33,760 knock out animals cells, mice, as well as their cells. 648 00:42:33,760 --> 00:42:37,280 And the interesting thing we found was 649 00:42:37,280 --> 00:42:42,280 that when you remove the ability for the M1 to express 650 00:42:46,620 --> 00:42:50,060 or signal the CXCR10 to CXCR3 651 00:42:53,446 --> 00:42:56,220 that macrophage simulation 652 00:42:56,220 --> 00:43:01,000 of fibroblasts is completely changed. 653 00:43:01,000 --> 00:43:06,000 And in fact, CXCR3 is required on the macrophages 654 00:43:06,670 --> 00:43:11,360 for the fibroblast to simulate that pro-fibrotic response 655 00:43:11,360 --> 00:43:15,690 that pro-inflammatory response that we see in the fibroblast 656 00:43:15,690 --> 00:43:18,803 and the opposite was true for that of the M2. 657 00:43:22,420 --> 00:43:25,370 And so there is a picture that is emerging, 658 00:43:25,370 --> 00:43:30,370 and I will tell those who are not familiar in this area 659 00:43:31,040 --> 00:43:35,890 that it does challenge the current dogma in some way, 660 00:43:35,890 --> 00:43:39,300 in which, we're seeing this shift 661 00:43:40,149 --> 00:43:43,226 and that fibroblasts to be a bigger player 662 00:43:43,226 --> 00:43:47,150 in the tissue remodeling or the inflammation role 663 00:43:47,150 --> 00:43:50,040 of tissue remodeling, but more importantly 664 00:43:50,040 --> 00:43:55,040 that the CXCR3, CXCL10 signaling access is a key modulator 665 00:43:55,353 --> 00:43:58,263 that is modulating this particular feedback. 666 00:44:01,450 --> 00:44:05,100 So last, in the last few minutes, I wanna, 667 00:44:05,100 --> 00:44:07,910 move forward and just kind of briefly tell you 668 00:44:07,910 --> 00:44:11,110 about how we take this information 669 00:44:11,110 --> 00:44:15,680 even though it was really condensed and generalized 670 00:44:15,680 --> 00:44:17,470 for the purpose of this presentation, 671 00:44:17,470 --> 00:44:18,960 but how we take this information 672 00:44:18,960 --> 00:44:21,810 and move it into a therapeutic. 673 00:44:21,810 --> 00:44:26,810 So disease relevant chemokines have long been established 674 00:44:27,320 --> 00:44:31,670 as disease relevant, their biomarkers, as I mentioned 675 00:44:31,670 --> 00:44:35,160 and they are multifactorial and Genesis inflammation 676 00:44:35,160 --> 00:44:38,570 tissue remodeling play a major role in there. 677 00:44:38,570 --> 00:44:42,040 And then they're also are small, 678 00:44:42,040 --> 00:44:46,560 and so delivery and synthesis are key. 679 00:44:47,773 --> 00:44:52,080 So they don't necessarily they make a great drug target 680 00:44:52,080 --> 00:44:57,080 or therapeutic potential because of their small size 681 00:44:58,040 --> 00:45:01,310 and ability to not necessarily initiate 682 00:45:01,310 --> 00:45:02,993 a strong immune response. 683 00:45:04,400 --> 00:45:09,400 We have established several different chemokine technologies 684 00:45:09,770 --> 00:45:14,770 and some have been, where we've developed 685 00:45:14,900 --> 00:45:18,710 chemokine cocktails to allow them to work in synergy. 686 00:45:18,710 --> 00:45:23,710 But I want to focus on both the remainder of the talk on, 687 00:45:24,630 --> 00:45:29,630 in this particular chemokine which is more of a single use 688 00:45:29,940 --> 00:45:31,100 that we've developed. 689 00:45:31,100 --> 00:45:33,910 So how do you develop these, right? 690 00:45:33,910 --> 00:45:38,270 So I mentioned that the same chemokine CXCL10 691 00:45:38,270 --> 00:45:43,270 can actually modulate multiple cell types, 692 00:45:43,620 --> 00:45:45,640 but also in different manners. 693 00:45:45,640 --> 00:45:50,640 And where, how do you develop a targeted therapeutic 694 00:45:51,220 --> 00:45:55,240 to actually meet the needs 695 00:45:55,240 --> 00:46:00,240 of the molecular process of interest? 696 00:46:00,960 --> 00:46:04,790 And so this is when we begin to look at 697 00:46:07,220 --> 00:46:10,750 the structure of the chemokine 698 00:46:10,750 --> 00:46:14,430 and this biological complexity 699 00:46:14,430 --> 00:46:18,440 and begin to really try to fragment and dissect 700 00:46:18,440 --> 00:46:23,440 potential fragments that are specific 701 00:46:24,340 --> 00:46:28,830 for the induction of a particular process. 702 00:46:28,830 --> 00:46:30,743 And so I don't do that. 703 00:46:31,630 --> 00:46:32,560 That's not my area 704 00:46:32,560 --> 00:46:34,903 but I work with a great team of biochemists. 705 00:46:36,120 --> 00:46:39,160 And to date we've developed over in patents, 706 00:46:39,160 --> 00:46:42,617 over 40 different chemokine targets 707 00:46:42,617 --> 00:46:44,570 some agonists and antagonists. 708 00:46:44,570 --> 00:46:46,120 And what I'm showing you here are those 709 00:46:46,120 --> 00:46:50,490 that we've developed that are agonist and antagonist 710 00:46:50,490 --> 00:46:54,033 to the CXCR3 or CXCL10 signaling access. 711 00:46:57,020 --> 00:47:00,680 And so for CXCL10, for simplicity purposes, 712 00:47:00,680 --> 00:47:03,640 what we found was it really was the chemokines terminal, 713 00:47:03,640 --> 00:47:08,110 the N-terminus of it was the anti region 714 00:47:09,255 --> 00:47:13,533 that was the area that induce the inhibition 715 00:47:15,120 --> 00:47:19,000 of grow factor migration that we saw 716 00:47:19,000 --> 00:47:22,290 in induce migration that we saw in the fibroblasts 717 00:47:22,290 --> 00:47:24,640 and epidemial cells for that matter. 718 00:47:24,640 --> 00:47:28,090 And so one of our first peptides that we developed 719 00:47:28,090 --> 00:47:32,280 was a CXCL10 which is called CXCL10P. 720 00:47:32,280 --> 00:47:36,170 We've also done additional fragments and found 721 00:47:36,170 --> 00:47:39,950 anti pro-inflammatory portions, 722 00:47:39,950 --> 00:47:43,163 and have developed those as well. 723 00:47:48,550 --> 00:47:53,550 The targets that we have tested thus far 724 00:47:53,840 --> 00:47:56,070 are myocardial infarction. 725 00:47:56,070 --> 00:48:01,070 As I mentioned, the in-stage heart failure 726 00:48:01,640 --> 00:48:04,130 which is due to fibrosis. 727 00:48:04,130 --> 00:48:09,130 And so we've targeted that, we've also done targets and have 728 00:48:11,920 --> 00:48:16,050 licensed this to, with a pharmaceutical company 729 00:48:16,970 --> 00:48:19,730 to target IPF. 730 00:48:19,730 --> 00:48:23,040 So that's now being used. 731 00:48:23,040 --> 00:48:27,967 We are dually targeting two pathways, both the TGF beta 732 00:48:29,000 --> 00:48:33,463 and the angiogenesis with a peptide. 733 00:48:40,649 --> 00:48:43,040 And definitely we have looked at the mechanisms 734 00:48:44,460 --> 00:48:46,280 in which we are being a developer 735 00:48:46,280 --> 00:48:49,640 or the understanding of how COVID-19 736 00:48:49,640 --> 00:48:54,640 or the SARS virus is manifesting. 737 00:48:56,980 --> 00:48:59,060 And we looked at the cytokine storm. 738 00:48:59,060 --> 00:49:01,490 And in fact, we found that there is these 739 00:49:02,510 --> 00:49:07,510 convergent pathways that meet because the end result 740 00:49:08,680 --> 00:49:13,680 of that cytokine storm is in many cases 741 00:49:13,860 --> 00:49:18,710 fibrosis or a fibrotic co-morbidity as a particular organ. 742 00:49:18,710 --> 00:49:22,600 And we've developed potential targets for that 743 00:49:22,600 --> 00:49:27,600 that are now ongoing and will be tested very soon 744 00:49:28,370 --> 00:49:30,283 in a few viral models. 745 00:49:31,400 --> 00:49:35,470 So just so I have time for a few questions, 746 00:49:35,470 --> 00:49:40,300 I just want to say the current thoughts of where we are now, 747 00:49:40,300 --> 00:49:41,773 chemokines are important. 748 00:49:42,650 --> 00:49:47,520 We're not alone, in thinking that we have 749 00:49:47,520 --> 00:49:51,500 put at the forefront the investigation of CXCL10 750 00:49:51,500 --> 00:49:55,210 as a potential target that remodeling, crosstalk 751 00:49:55,210 --> 00:49:58,660 between the key cell types that are involved 752 00:49:58,660 --> 00:50:00,843 in tissue repair. 753 00:50:02,350 --> 00:50:07,350 We have learned, ways to develop these fibromatic 754 00:50:09,160 --> 00:50:13,230 targeted therapies in development of peptides, 755 00:50:13,230 --> 00:50:15,340 but we still have a long way to go 756 00:50:15,340 --> 00:50:19,470 because even developing these, and it's really interesting 757 00:50:19,470 --> 00:50:24,470 that our SARS, COVID indication really hits home 758 00:50:25,100 --> 00:50:29,120 and where the potential of this could go 759 00:50:29,120 --> 00:50:31,633 but it also lets us know, 760 00:50:32,520 --> 00:50:35,040 other mechanisms that need to be investigated 761 00:50:35,040 --> 00:50:38,190 but really how we can simultaneously modulate 762 00:50:38,190 --> 00:50:43,190 to potential conversion pathways 763 00:50:44,500 --> 00:50:46,850 in the treatment and that of, 764 00:50:46,850 --> 00:50:50,430 those of the inflammatory and fibrotic mechanisms. 765 00:50:53,730 --> 00:50:57,217 So just so I have time for questions 766 00:50:57,217 --> 00:51:00,040 I've kind of already gone over the impact. 767 00:51:00,040 --> 00:51:04,560 I don't want to reiterate that, but we do think 768 00:51:04,560 --> 00:51:09,560 that the continued investigation of this work will allow, 769 00:51:11,060 --> 00:51:12,930 hopefully allow us to translate this 770 00:51:12,930 --> 00:51:15,550 into targeted individualized approaches, 771 00:51:15,550 --> 00:51:19,530 using the understanding of chemokine biology 772 00:51:19,530 --> 00:51:21,533 and peptide synthesis. 773 00:51:22,760 --> 00:51:27,300 And so this is just my, the group that I've worked with, 774 00:51:27,300 --> 00:51:29,580 I have fabulous collaborators. 775 00:51:29,580 --> 00:51:32,680 I actually just talk about this. 776 00:51:32,680 --> 00:51:36,380 Most of the brain power and the think tank 777 00:51:36,380 --> 00:51:39,284 comes from the group that you see here. 778 00:51:39,284 --> 00:51:41,890 And they have really been amazing 779 00:51:41,890 --> 00:51:43,713 and across the country, 780 00:51:44,710 --> 00:51:48,940 and I think all projects go much better 781 00:51:48,940 --> 00:51:51,270 and smoother when you have a great team 782 00:51:51,270 --> 00:51:54,610 that you're working with, experts in the field. 783 00:51:54,610 --> 00:51:58,610 So with that, I will entertain any questions 784 00:52:02,260 --> 00:52:03,093 - Dr. Yates. 785 00:52:03,093 --> 00:52:04,150 This is Nelson ScottGale. 786 00:52:04,150 --> 00:52:05,873 Thank you very much for your talk. 787 00:52:07,040 --> 00:52:08,790 And I wanted to start off 788 00:52:10,520 --> 00:52:13,363 with sort of a general question. 789 00:52:15,620 --> 00:52:18,030 What are treatments that patients can do 790 00:52:18,030 --> 00:52:22,550 to promote normal healing in fibrosis and also 791 00:52:22,550 --> 00:52:25,870 are there any things that people can do 792 00:52:25,870 --> 00:52:29,253 to change their chemokine secretions? 793 00:52:30,388 --> 00:52:35,040 - (laughs) Well, that's the first time 794 00:52:35,040 --> 00:52:37,120 anyone's ever asked me that, like, how do you change 795 00:52:37,120 --> 00:52:39,320 your chemokine in patients? 796 00:52:39,320 --> 00:52:42,700 I have to say that I have to really investigate in that. 797 00:52:42,700 --> 00:52:45,800 I don't know what you could do holistically 798 00:52:46,770 --> 00:52:50,380 to change your chemokine. 799 00:52:50,380 --> 00:52:55,380 Now I can say scientifically how we can reduce inflammation. 800 00:52:57,700 --> 00:52:59,807 We know different ways to do that. 801 00:52:59,807 --> 00:53:04,807 We know different ways to promote healing. 802 00:53:06,323 --> 00:53:10,983 And there are various, 803 00:53:13,600 --> 00:53:15,080 I don't want to promote 804 00:53:15,080 --> 00:53:17,410 any one over the other, but there are various molecules 805 00:53:17,410 --> 00:53:21,240 that we know, vitamin D is one 806 00:53:21,240 --> 00:53:22,790 that initially comes to mind 807 00:53:22,790 --> 00:53:26,860 that plays a major role in both inflammation, 808 00:53:26,860 --> 00:53:28,800 as well as fibrosis. 809 00:53:28,800 --> 00:53:33,800 And we know that deficiency in this can cause huge 810 00:53:37,080 --> 00:53:41,280 risk factors, increased risk factors for various diseases 811 00:53:41,280 --> 00:53:46,280 that of diabetes, as well as COVID-19 and fibrosis. 812 00:53:47,610 --> 00:53:51,043 So that part of your question, I would say, 813 00:53:52,128 --> 00:53:55,740 we have some understanding how we can reduce inflammation, 814 00:53:55,740 --> 00:53:58,960 but I don't think we're there yet, 815 00:53:58,960 --> 00:54:02,770 provide a cocktail and say," hey, go home and drink this 816 00:54:02,770 --> 00:54:03,770 and you'll be good." 817 00:54:04,700 --> 00:54:09,600 Because there are underlying factors here, 818 00:54:09,600 --> 00:54:11,460 because fibrosis, most fibroid 819 00:54:14,210 --> 00:54:16,060 disease is a co-morbidity 820 00:54:16,060 --> 00:54:19,210 and there's another source, whether it's from diabetes 821 00:54:20,240 --> 00:54:23,860 heart attack, autoimmune disease. 822 00:54:23,860 --> 00:54:26,470 And so that, I think we'll have to be this force 823 00:54:26,470 --> 00:54:29,020 of the treatment if you want to do it holistically. 824 00:54:31,730 --> 00:54:34,460 - Okay Yates, thanks for a very informative talk. 825 00:54:34,460 --> 00:54:36,470 I have a question for you now, 826 00:54:36,470 --> 00:54:38,690 what part of the process is abnormal 827 00:54:38,690 --> 00:54:41,183 when healing tissues turn into bone? 828 00:54:42,650 --> 00:54:45,640 - When healing, say that again. 829 00:54:45,640 --> 00:54:48,140 - What part of the process is abnormal 830 00:54:48,140 --> 00:54:51,640 when healing tissues turn into bone? 831 00:54:51,640 --> 00:54:56,640 - Well, so there, if it could go awry at different stages. 832 00:54:56,950 --> 00:54:59,680 And so when, if we kind of go back 833 00:54:59,680 --> 00:55:04,680 to one of my initial slides, I can think of better. 834 00:55:11,850 --> 00:55:13,323 Okay. Maybe not. 835 00:55:14,200 --> 00:55:18,783 Yeah. So one of the earlier slides, you have this, 836 00:55:19,870 --> 00:55:23,640 this inflammation and the proliferative phase, right? 837 00:55:23,640 --> 00:55:25,040 And they do overlap. 838 00:55:25,040 --> 00:55:27,370 As I mentioned, they're not mutually exclusive. 839 00:55:27,370 --> 00:55:29,050 We always show it that way 840 00:55:29,050 --> 00:55:31,730 and like these really nice find neat stages 841 00:55:31,730 --> 00:55:34,350 but it's much more dynamic than that. 842 00:55:34,350 --> 00:55:37,110 And if you think about the diet, 843 00:55:37,110 --> 00:55:40,320 the theory of dynamic reciprocity, 844 00:55:40,320 --> 00:55:45,320 there are several stages in which this could go awry, right? 845 00:55:45,420 --> 00:55:48,320 If you go awry at the initiation stage 846 00:55:48,320 --> 00:55:53,320 between inflammation and proliferation, if that imbalance 847 00:55:53,650 --> 00:55:58,650 as I mentioned of metallic proteases occurs in there 848 00:56:00,120 --> 00:56:02,606 the tissue is not being de gradated. 849 00:56:02,606 --> 00:56:06,880 And so now you have this increase of 850 00:56:08,760 --> 00:56:13,760 and synthesis of your osteoblasts, and in the case of bone 851 00:56:15,060 --> 00:56:17,810 that are producing 852 00:56:19,900 --> 00:56:21,740 bone matrix, 853 00:56:21,740 --> 00:56:24,280 it won't shut it off there's no degragation 854 00:56:24,280 --> 00:56:26,090 of that to resolve it. 855 00:56:26,090 --> 00:56:29,707 And so, that can happen at between 856 00:56:29,707 --> 00:56:32,210 the inflammation proliferation phase. 857 00:56:32,210 --> 00:56:34,680 But it also can happen later on 858 00:56:34,680 --> 00:56:38,853 between that proliferation in remodeling. 859 00:56:40,740 --> 00:56:42,620 Yeah. It is complicated. 860 00:56:42,620 --> 00:56:46,253 And, but interesting dynamic. 861 00:56:49,090 --> 00:56:51,178 - Dr. Yates, one last question, I think, 862 00:56:51,178 --> 00:56:54,460 do you know anything about how water plays a role 863 00:56:54,460 --> 00:56:55,470 in wound healing? 864 00:56:55,470 --> 00:56:58,700 When I have a cut I think it always seems more healed 865 00:56:58,700 --> 00:57:00,503 after I shower or swim. 866 00:57:02,540 --> 00:57:05,583 - Well, I will say is water is maybe moisture. 867 00:57:06,870 --> 00:57:10,620 So when I teach anatomy physiology 868 00:57:10,620 --> 00:57:13,600 to first year nursing students, 869 00:57:13,600 --> 00:57:17,493 I start off with this corny joke and tell them, one, 870 00:57:18,470 --> 00:57:19,730 beauty really is skin deep. 871 00:57:19,730 --> 00:57:22,700 Your first layer of skin is dead. 872 00:57:22,700 --> 00:57:24,310 So that is true. 873 00:57:24,310 --> 00:57:29,010 It is skin deep, but also listen to your mom when she says, 874 00:57:29,010 --> 00:57:31,470 don't take your scab, right? 875 00:57:31,470 --> 00:57:35,150 Because it's not done healing. 876 00:57:35,150 --> 00:57:38,520 And so I showed a picture of but I didn't describe it 877 00:57:38,520 --> 00:57:42,230 in detail, but what happens when you cut yourself, right? 878 00:57:42,230 --> 00:57:47,180 You have this denuded area, that epidermal layer is now, 879 00:57:47,180 --> 00:57:52,180 has to begin to migrate from the two leading edges, right? 880 00:57:52,210 --> 00:57:55,584 And your neutrophils and your macrophages 881 00:57:55,584 --> 00:57:58,500 are trying to ward off all, any bacterial infection 882 00:57:58,500 --> 00:58:01,678 or debris that may have gotten in there kill off 883 00:58:01,678 --> 00:58:02,790 given all the dead tissue. 884 00:58:02,790 --> 00:58:07,210 And as they begin to do that and they die off 885 00:58:07,210 --> 00:58:09,883 and create this clot, it creates the scab. 886 00:58:11,050 --> 00:58:15,170 But at the same time your two leading edges 887 00:58:15,170 --> 00:58:19,030 have to come back and knit for closure. 888 00:58:19,030 --> 00:58:20,690 And if you pick that scab 889 00:58:20,690 --> 00:58:24,420 that clot off too soon, they haven't closed yet. 890 00:58:24,420 --> 00:58:27,080 And so that's why you bleed again. 891 00:58:27,080 --> 00:58:30,500 Well, one of the things that we do know that promotes the 892 00:58:30,500 --> 00:58:34,623 or increases the speed of that closure is moisture. 893 00:58:36,898 --> 00:58:39,180 (mumbles) 894 00:58:39,180 --> 00:58:42,721 - Dr. Yates, a final question before I pass you back 895 00:58:42,721 --> 00:58:44,370 to your colleague, Dr. Schreiner. 896 00:58:44,370 --> 00:58:47,630 Do you believe that nanotechnology, biodegradable, 897 00:58:47,630 --> 00:58:51,040 nanosscaffolds and or nanofibers 898 00:58:51,040 --> 00:58:52,853 hold promise for the future? 899 00:58:53,860 --> 00:58:58,860 - Absolutely. And I am a little biased in that. 900 00:58:59,800 --> 00:59:03,930 Our group has developed a few polymers, 901 00:59:03,930 --> 00:59:07,672 biodegradable polymers that degrade 902 00:59:07,672 --> 00:59:10,270 and they integrate into the tissue 903 00:59:10,270 --> 00:59:13,790 and degrade within 14 days to promote healing. 904 00:59:13,790 --> 00:59:17,230 And in fact, it acts as a bio responsive. 905 00:59:17,230 --> 00:59:20,900 We call it a bio band-aid because it will seal the wound 906 00:59:20,900 --> 00:59:23,750 but it will also respond to the tissue. 907 00:59:23,750 --> 00:59:25,790 We've gone as far as, 908 00:59:25,790 --> 00:59:30,790 introducing cell types of transplant into the polymer. 909 00:59:30,910 --> 00:59:34,360 And this is similar use of nanotechnology 910 00:59:34,360 --> 00:59:38,910 that you can use to then signal to act almost 911 00:59:38,910 --> 00:59:42,290 like this artificial smart cell that can signal 912 00:59:42,290 --> 00:59:45,680 to the wound and respond to the individual environment 913 00:59:45,680 --> 00:59:48,030 because everyone's wound environment is different. 914 00:59:48,030 --> 00:59:50,260 And so we all respond differently. 915 00:59:50,260 --> 00:59:53,260 So if we can understand the mechanism 916 00:59:53,260 --> 00:59:58,260 and the pathogenesis and find a way to treat 917 01:00:00,360 --> 01:00:03,550 so that the treatment is by our responses, 918 01:00:03,550 --> 01:00:05,420 I think we can cast a wider net 919 01:00:05,420 --> 01:00:08,520 in personalizing our treatments. 920 01:00:08,520 --> 01:00:10,600 So yes, the short answer is yes 921 01:00:10,600 --> 01:00:15,600 I do think it holds great promise and especially 922 01:00:15,930 --> 01:00:17,933 in the area of, you know, 923 01:00:19,570 --> 01:00:21,970 controlled drug delivery, 924 01:00:21,970 --> 01:00:24,573 therapeutic delivery, as well as precision. 925 01:00:26,520 --> 01:00:28,910 - Thank you. I now invite Dr. Schreiner 926 01:00:28,910 --> 01:00:32,630 to formally thank you for a wonderful talk. 927 01:00:32,630 --> 01:00:35,308 - Yeah. So on behalf of the Darwin festival committee 928 01:00:35,308 --> 01:00:38,640 and the bio department, thank you so much for your talk. 929 01:00:38,640 --> 01:00:40,193 As an immunologist I was like, 930 01:00:41,662 --> 01:00:43,910 am used to all the talking, and I'm biased. 931 01:00:43,910 --> 01:00:45,130 I usually talk about the macrophage. 932 01:00:45,130 --> 01:00:45,963 So now I'm gonna have to like 933 01:00:45,963 --> 01:00:48,130 make sure I really emphasis the fibroblasts. 934 01:00:49,084 --> 01:00:51,650 So, so thank you again 935 01:00:51,650 --> 01:00:55,350 for accepting the invitation and a wonderful talk. 936 01:00:55,350 --> 01:00:59,640 - Now I know, it's actually an honor and I thank you 937 01:00:59,640 --> 01:01:00,776 for inviting me. 938 01:01:00,776 --> 01:01:03,311 This is great and I wish the best of my, 939 01:01:03,311 --> 01:01:07,883 I look forward to attending next year as a viewer. 940 01:01:12,450 --> 01:01:15,180 - Thank you everyone, that concludes this morning's webinar. 941 01:01:15,180 --> 01:01:17,030 We have another one at 2:00 PM 942 01:01:17,030 --> 01:01:19,380 and hopefully we'll see you there. Bye-bye. 943 01:01:19,380 --> 01:01:20,717 - Thank you. Bye-bye.