Kenneth D. Poss, Ph.D. (Massachusetts Institute of Technology)
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.
We study the initial morphogenesis and injury-induced regeneration of several tissues in zebrafish. The majority of our student and postdoc projects focus on (but are not limited to) adult heart and fins.
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 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 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, with goals to acquire and quantify live cellular and subcellular events in regenerating complex tissues.
Goldman JA, Kuzu G, Lee N, Karasik J, Gemberling M, Foglia MJ, Karra R, Dickson AL, Sun F, Tolstorukov MY, Poss KD. (2017) Resolving Heart Regeneration by Replacement Histone Profiling. Dev Cell. 27;40(4):392-404.e5.
Karra R, Poss KD. (2017) Redirecting cardiac growth mechanisms for therapeutic regeneration. J Clin Invest. 1;127(2):427-436.
Tornini VA, Puliafito A, Slota LA, Thompson JD, Nachtrab G, Kaushik AL, Kapsimali M, Primo L, Di Talia S, Poss KD. (2016) Live Monitoring of Blastemal Cell Contributions during Appendage Regeneration. Curr Biol. 21;26(22):2981-2991.
Mokalled MH, Patra C, Dickson AL, Endo T, Stainier DY, Poss KD. (2016) Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science. 4;354(6312):630-634. .
Nichols JT, Blanco-Sánchez B, Brooks EP, Parthasarathy R, Dowd J, Subramanian A, Nachtrab G, Poss KD, Schilling TF, Kimmel CB. (2016) Ligament versus bone cell identity in the zebrafish hyoid skeleton is regulated by mef2ca. Development. 1;143(23):4430-4440.
Di Talia S, Poss KD. (2016) Monitoring Tissue Regeneration at Single-Cell Resolution. Cell Stem Cell. 6;19(4):428-431.
Wang J, Poss KD. (2016) Methodologies for Inducing Cardiac Injury and Assaying Regeneration in Adult Zebrafish. Methods Mol Biol. 1451:225-35.
Han Y, Poss KD. (2016) Accessories to Limb Regeneration. Dev Cell. 23;37(4):297-8.
Cao J, Poss KD. (2016) Explant culture of adult zebrafish hearts for epicardial regeneration studies. Nat Protoc. 11(5):872-81.
Kang J, Hu J, Karra R, Dickson AL, Tornini VA, Nachtrab G, Gemberling M, Goldman JA, Black BL, Poss KD. (2016) Modulation of tissue repair by regeneration enhancer elements. Nature. 14;532(7598):201-6.