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Signals Regulating Stem Cell Self-renewal
What are cellular and molecular mechanisms that control tissue regeneration in vivo? Stem cells ensure tissue renewal in most adult tissues, and their activities are under the precise control of signals from specific local microenvironments, or niches. The ability to manipulate stem identity and behavior is a long-standing goal of regenerative medicine. Understanding how endogenous niches work is essential for fulfilling this goal, but most niches are poorly defined.
The Drosophila testis contains a well-characterized niche. In this tissue, sperm-producing germline stem cells attach to a cluster of non-dividing somatic cells called the hub. The hub secretes local cytokines that are received by adjacent stem cells, promoting their identity (or maintenance). When germline stem cells divide, their daughters are displaced away from the hub (or out of the niche) and enter the differentiation program. Somatic stem cells also adhere to the hub, producing somatic support cells that guide germ cell differentiation. Cells within this niche can be tracked in real time at the single cell level using biosensors, and a rich assortment of genetic tools makes addressing fundamental questions about stem cells more feasible in this system than many others. Several conserved aspects of the biology of stem cell niches are emerging from studying the Drosophila spermatogonial stem cell niche.
Discovering the signals that promote stem cell renewal in the fly testis has made it possible to manipulate stem cell function in vivo. This, in turn, has revealed several unexpected insights about how niches function in response to challenges. An emerging theme is that stem cells, and even niche cells, have a surprising degree of plasticity in vivo. For example, eliminating germline stem cells causes differentiating germ cells to dedifferentiate into new germline stem cells. In contrast, elimination of somatic stem cells causes quiescent hub cells to transdifferentiate into replacement somatic stem cells. Interestingly, eliminating hub cells does not provoke any type of regenerative response. We are currently seeking the molecular and cellular circuits controlling these cell fate transitions. We also study competition amongst stem cells, and their resistance to environmental stresses, including DNA damage. While all cells must maintain genomic integrity, this problem is particularly interesting in germline stem cells - the only stem cells to transmit the genome to future generations.
Ma Q, de Cuevas M, Matunis EL. 2016. Chinmo is sufficient to induce male fate in somatic cells of the adult Drosophila ovary. Development 43(5):754-63.
Greenspan LJ, de Cuevas M, Matunis E. 2015. Genetics of gonadal stem cell renewal. Annual Review of Cell and Developmental Biology 31:291-315.
Ma Q, Wawersik M, Matunis EL. 2014. The Jak-STAT target Chinmo prevents sex transformation of adult stem cells in the Drosophila testis niche. Developmental Cell 31(4):474-86.
Stine RR, Greenspan LJ, Ramachandran KV, Matunis EL. 2014. Coordinate regulation of stem cell competition by Slit-Robo and JAK-STAT signaling in the Drosophila testis. PLoS Genetics 10(11):e1004713.
Hétié P, de Cuevas M, Matunis E. 2014. Conversion of quiescent niche cells to somatic stem cells causes ectopic niche formation in the Drosophila testis. Cell Reports 7(3):715-21.
Sheng XR, Matunis EL. 2011. Live imaging of the Drosophila spermatogonial stem cell niche reveals novel mechanisms regulating germline stem cell output. Development 16:3367-3376.
Cherry CM, Matunis EL. 2010. Epigenetic regulation of stem cell maintenance in the Drosophila testis via the nucleosome remodeling factor NURF. Cell Stem Cell 6:557-567.
Issigonis M, Tulina N, de Cuevas M, Brawley C, Sandler L, Matunis EL. 2009. JAK-STAT signal inhibition regulates competition within the Drosophila testis stem cell niche. Science 326:153-6.
Sheng XR, Brawley CM, Matunis EL. 2009. Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis. Cell Stem Cell 5:191-203.
Sheng XR, Posenau T, Gumulak-Smith JJ, Matunis EL, Van Doren M, Wawersik M. 2009. Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis. Developmental Biology 334:335-344.
Buszczak M, Paterno S, Lighthouse D, Bachman J, Plank J, Owen S, Skora A, Nystul T, Ohlstein B, Allen A, Wilhelm J, Murphy T, Levis B, Matunis. EL, Srivali N, Hoskins R, Spradling A. 2007. The Carnegie protein trap library: a versatile tool for Drosophila developmental studies. Genetics 175:1501-1531.
Terry NA, Tulina N, Matunis EL., DiNardo S. 2006. Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Developmental Biology 294:246-257.
Wawersik M, Milutinovich A, Matunis EL,Williams B, Van Doren M. 2005. Somatic control of germline sexual differentiation is mediated by the JAK/STAT pathway. Nature 436:563-567.
Brawley C,Matunis EL. 2004. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304:1331-1334.
Tulina N, Matunis EL. 2001. Control of Stem cell self-renewal in Drosophila spermatogenesis by Jak-STAT signaling. Science 294: 2546-2549.