Kenneth D. Poss, Ph.D. (Massachusetts Institute of Technology)
James B. Duke Professor, Cell Biology
Early Career Scientist, Howard Hughes Medical Institute
349 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 their use to reveal concepts and mechanisms of regeneration.
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. Several 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 initially 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. We are continuing to explore how muscle and non-muscle cells respond to injury and orchestrate regeneration.
The study of cardiac repair in mammals has surged in the past few years. Most notably, increased attention has been paid to cardiomyocyte division in adult mice and humans, and recent evidence indicates that cardiomyocyte proliferation is stimulated at low levels after injury to the adult mouse heart. Studies of the epicardium in adult mice have similarly mirrored findings in zebrafish, and epicardial cells are now being implicated in mammalian cardiac repair mechanisms. Thus, regenerative machinery present in zebrafish has analogous components in mammals, but is not activated to the same extent for significant regeneration. Together, models like zebrafish and neonatal/adult mice have great potential to reveal methods to gauge and stimulate human heart regeneration.
Zebrafish fins are transparent, intricately patterned structures, making them tractable for asking fundamental questions about complex tissue regeneration. Within two weeks after amputation of the tail 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 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, based in part on some of our recently published clonal analyses of zebrafish heart morphogenesis.
Gemberling, M., Karra, R., Dickson, A. L., and Poss, K. D. (2015). Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. eLife 4:e05871
Wang, J., Cao, J., Dickson, A. L., and Poss, K. D. (2015). Epicardial regeneration is guided by cardiac outflow tract and Hedgehog signaling. Nature 522, 226-230.
Tornini, V.A. and Poss, K.D. (2014) Keeping at arm's length during regeneration. Dev Cell 29(2):139-145
Chen, C. H., Durand, E., Wang, J., Zon, L. I., and Poss, K. D. (2013) zebraflash transgenic lines for in vivo bioluminescence imaging of stem cells and regeneration in adult zebrafish. Development 140(24):4988-4997
Kang, J., Nachtrab, G., and Poss, K. D. (2013) Local Dkk1 crosstalk from breeding ornaments impedes regeneration of injured male zebrafish fins. Dev Cell 27:19-31
Wang J, Karra R, Dickson AL, Poss KD (2013) Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. Dev Biol. 382(2):427-435
Johnson AN, Mokalled MH, Valera JM, Poss KD, Olson EN (2013) Post-transcriptional regulation of myotube elongation and myogenesis by Hoi Polloi. Development. 140(17):3645-56
Gemberling M, Bailey TJ, Hyde DR, Poss KD (2013) The zebrafish as a model for complex tissue regeneration. Trends Genet. S0168-9525(13)00113-3
Nachtrab G, Kikuchi K, Tornini VA, Poss KD (2013) Transcriptional components of anteroposterior positional information during zebrafish fin regeneration. Development. 140(18):3754-64
Fang Y, Gupta V, Karra R, Holdway JE, Kikuchi K, Poss KD (2013) Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury reponse required for zebrafish heart regeneration. Proc Natl Acad Sci USA. 110(33):13416-21
Gupta V, Gemberling M, Karra R, Rosenfeld GE, Evans T, Poss KD (2013) An injury-responsive gata4 program shapes the zebrafish cardiac ventricle. Curr Biol 23(13):1221-7
Le X, Pugach EK, Hettmer S, Storer NY, Liu J, Wills AA, DiBiase A, Chen EY, Ignatius MS, Poss KD, Wagers AJ, Langenau DM, Zon LI (2013) A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development. Development. 140(11):2354-64
Guner-Ataman B, Paffett-Lugassy N, Adams MS, Nevis KR, Jahangiri L, Obregon P, Kikuchi K, Poss KD, Burns CE, Burns CG (2013) Zebrafish second heart field development relies on progenitor specification in anterior lateral plate mesoderm and nkx2.5 function. Development. 140(3):660-6
Choi W.Y., Gemberling M., Wang J., Holdway J.E., Shen M.C., Karlstrom R.O., and Poss, K.D. (2013). In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration. Development 140, 660-666.
Kikuchi, K and Poss, K.D. (2012). Cardiac regenerative capacity and mechanisms. Annual Review of Cell and Developmental Biology 28, 719-741.