Kenneth D. Poss, Ph.D. (Massachusetts Institute of Technology)
James B. Duke Professor of Regenerative Biology
Professor of Biology
Professor in Medicine
Director of the Duke Regeneration Center
466 Nanaline Duke Building, Box 3709
Duke University Medical Center
Durham, NC 27710
How and why tissue regeneration does (or does not) occur are critical questions. The biology of regeneration remains both challenging and fascinating, and new discoveries have the potential to impact clinical outcomes of many diseases of organ damage, including heart failure, Alzheimer's disease, and diabetes.
It has been known for centuries that salamanders and fish regenerate complex tissues much more effectively than mammals. Zebrafish have emerged as a central model system for studying regeneration, due to their ability to regenerate myriad tissues and to the availability of molecular genetic tools. Over the past decade, our laboratory has spearheaded the use of zebrafish to reveal concepts and mechanisms of regeneration.
We study the initial morphogenesis and injury-induced regeneration of several tissues in zebrafish. Our student and postdoc projects investigate adult hearts, fins, spinal cord, skin, scales, and other tissues. We have also begun to test ideas in mammalian models.
There is little natural regeneration of the major structural cells of the adult mammalian heart, the cardiomyocytes, after injury. This regenerative shortcoming is highly relevant to human disease, given the high prevalence in the United States of ischemic myocardial infarction and heart failure. Many years ago, we introduced a model system approach to heart regeneration, by showing that adult zebrafish can regenerate new muscle lost after major cardiac injury. Since then, we have found that cardiac regeneration is not based on stem cells, but rather involves activation and proliferation of spared cardiac myocytes. We also have demonstrated multiple roles during heart regeneration for the epicardium, a thin epithelial layer enveloping the cardiac chambers, and the inner endothelial lining of the chambers called the endocardium. Together, models like zebrafish and neonatal mice have great potential to reveal methods to gauge and stimulate human heart regeneration. We are continuing to investigate how muscle and non-muscle cells respond to injury and orchestrate regeneration. Key issues include the identification of cardiomyocyte mitogens, the definition of gene regulatory elements that activate regeneration programs, and how to use fundamental mechanistic data in platforms to boost cardiac regenerative capacity in mammals. Our methods are exploratory and rely heavily on generation of new mutant and transgenic animals.
Zebrafish fins are transparent, intricately patterned structures, making them tractable for asking fundamental questions about complex tissue regeneration. Within two weeks after amputation of a fin, a series of healing, proliferation, and patterning events replaces bone, epidermis, blood vessels, nerves, and connective tissue mesenchyme. Our work on fin regeneration has helped establish the cellular origins of regenerated fin tissue, and it has identified new concepts and molecular mechanisms of appendage regeneration. We are pursuing informative mutants in fin regeneration, both by forward genetic screens and targeted gene editing. Also, we are developing new methods for imaging of key cellular and molecular events during regeneration, to acquire and quantify live cellular and subcellular events in regenerating complex tissues.
Spinal Cord Regeneration
The path to an effective regenerative therapy for spinal cord injury requires a combination of molecular, cellular, electrostimulatory, and engineering approaches, and can be guided by a deeper understanding of the inherent regenerative capacity of spinal cord tissue. Remarkably, only a handful of groups worldwide use adult zebrafish to investigate the innate ability for spinal regeneration. Just 6 to 8 weeks after a paralyzing injury that completing severs their spinal cord, zebrafish form new neurons, regrow axons, and recover the ability to swim. Importantly, these regenerative events proceed without massive scarring. Instead, following injury, specialized glial cells assist in forming a tissue bridge over the two severed ends, allowing axons to grow across the wound and reestablish crucial connections. We are exploring the underlying gene regulatory mechanisms of spinal cord regeneration, with the goals of finding key factors and regulatory sequences that initiate regeneration programs in spinal cord cell types.
Yan R, Cigliola V, Oonk KA, Petrover Z, DeLuca S, Wolfson DW, Vekstein A, Mendiola MA, Devlin G, Bishawi M, Gemberling MP, Sinha T, Sargent MA, York AJ, Shakked A, DeBenedittis P, Wendell DC, Ou J, Kang J, Goldman JA, Baht GS, Karra R, Williams AR, Bowles DE, Asokan A, Tzahor E, Gersbach CA, Molkentin JD, Bursac N, Black BL, Poss KD. An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair. Cell Stem Cell. 2023 Jan 5;30(1):96-111.e6. doi: 10.1016/j.stem.2022.11.012. Epub 2022 Dec 13. PMID: 36516837; PMCID: PMC9830588.
Haertter D, Wang X, Fogerson SM, Ramkumar N, Crawford JM, Poss KD, Di Talia S, Kiehart DP, Schmidt CF. DeepProjection: specific and robust projection of curved 2D tissue sheets from 3D microscopy using deep learning. Development. 2022 Nov 1;149(21):dev200621. doi: 10.1242/dev.200621. Epub 2022 Nov 11. PMID: 36178108; PMCID: PMC9686994.
Osorio-Méndez D, Miller A, Begeman IJ, Kurth A, Hagle R, Rolph D, Dickson AL, Chen CH, Halloran M, Poss KD, Kang J. Voltage-gated sodium channel scn8a is required for innervation and regeneration of amputated adult zebrafish fins. Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2200342119. doi: 10.1073/pnas.2200342119. Epub 2022 Jul 6. PMID: 35867745; PMCID: PMC9282381.
Sun J, Peterson EA, Wang AZ, Ou J, Smith KE, Poss KD, Wang J.Circulation. (2022). hapln1 Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration. Jun 2:101161CIRCULATIONAHA121055468. doi: 10.1161/CIRCULATIONAHA.121.055468. Online ahead of print.PMID: 35652354 Free article.
Das RN, Tevet Y, Safriel S, Han Y, Moshe N, Lambiase G, Bassi I, Nicenboim J, Brückner M, Hirsch D, Eilam-Altstadter R, Herzog W, Avraham R, Poss KD, Yaniv K.Nature. (2022). Generation of specialized blood vessels via lymphatic transdifferentiation. May 25. doi: 10.1038/s41586-022-04766-2. Online ahead of print.PMID: 35614218.
Sun F, Ou J, Shoffner AR, Luan Y, Yang H, Song L, Safi A, Cao J, Yue F, Crawford GE, Poss KD.Nat Cell Biol. (2022). Enhancer selection dictates gene expression responses in remote organs during tissue regeneration. May;24(5):685-696. doi: 10.1038/s41556-022-00906-y. Epub 2022 May 5.PMID: 35513710.
Vekstein AM, Wendell DC, DeLuca S, Yan R, Chen Y, Bishawi M, Devlin GW, Asokan A, Poss KD, Bowles DE, Williams AR, Bursac N.Front Cardiovasc Med. (2022). Targeted Delivery for Cardiac Regeneration: Comparison of Intra-coronary Infusion and Intra-myocardial Injection in Porcine Hearts. Feb 10;9:833335. doi: 10.3389/fcvm.2022.833335. eCollection 2022.PMID: 35224061 Free PMC article.
Cao Y, Xia Y, Balowski JJ, Ou J, Song L, Safi A, Curtis T, Crawford GE, Poss KD, Cao J.Development. (2022). Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration. Feb 15;149(4):dev200133. doi: 10.1242/dev.200133. Epub 2022 Feb 18.PMID: 35179181.
Gemberling MP, Siklenka K, Rodriguez E, Tonn-Eisinger KR, Barrera A, Liu F, Kantor A, Li L, Cigliola V, Hazlett MF, Williams CA, Bartelt LC, Madigan VJ, Bodle JC, Daniels H, Rouse DC, Hilton IB, Asokan A, Ciofani M, Poss KD, Reddy TE, West AE, Gersbach CA.Nat Methods. (2021). Transgenic mice for in vivo epigenome editing with CRISPR-based systems. Aug;18(8):965-974. doi: 10.1038/s41592-021-01207-2. Epub 2021 Aug 2.PMID: 34341582 Free PMC article.
Tseng TL, Wang YT, Tsao CY, Ke YT, Lee YC, Hsu HJ, Poss KD, Chen CH. (2021). The RNA helicase Ddx52 functions as a growth switch in juvenile zebrafish. Development. Aug 1;148(15):dev199578. doi: 10.1242/dev.199578. Epub 2021 Jul 29. PMID: 34323273.
Hayden LD, Poss KD, De Simone A, DiTalia S. (2021). Mathematical modeling of Erk activity waves in regenerating zebrafish scales. Biophys J. May 19:S0006-3495(21)00418-5.doi: 10.1016/j.bpj.2021.05.04. Online ahead of print. PMID:34022234.
Pronobis MI, Zheng S, Goldman, JA, Poss, KD. (2021). In vivo proximity labeling identifies cardiomyocyte protein networks during zebrafish heart regeneration. Elife. Mar 25: 10:e66079. doin: 10.7554/eLife.66079. Online ahead of print. PMID: 33764296.
Poss KD, Tanaka EM. (2021). A new society for regenerative biologists. Development. Feb 12;148(3):dev199474. doi: 10.1242/dev.199474. PMID: 33579756 No abstract available.
DeSimone A, Evanitsky MN, Hayden L, Cox BD, Wang J, Tornini VA, Ou J, Chao A, Poss KD, Di Talia, S. (2021). Control of osteoblast regeneration by a train of Erk activity waves. Nature. Jan 6. doi: 10.1038/s41586-020-03085-8. Online ahead of print.