Niche - Stem Cell Interactions

Stem cells hold the key to the continual renewal of many of our tissues. In addition, the manipulation of these cells holds much promise for regenerative medicine. Unfortunately, there are severe limitations in our knowledge of the regulation of stem cells and that compromises our understanding of normal tissue renewal, and restrains their clinical utility. To uncover the general principles of stem cell regulation, we study adult stem cells within their natural environment, the niche, by using Drosophila spermatogenesis as a model system. Among the strengths of this system are the molecular markers and techniques to unambiguously identify the niche cells, as well the two stem cell lineages that maintain this tissue. This allows us to apply both genetic and genome-scale molecular approaches to uncover novel factors governing niche-stem cell interactions, self-renewal, differentiation, proliferation and stem cell aging. Most importantly, it allows for high-resolution, real-time imaging of the initial assembly of the niche, and of stem cell behavior. Given the deep conservation of mechanisms across species, we are confident that concepts revealed by our studies will apply to mammalian stem cell – niche interactions.

The Testis Niche

The photo above shows the tip of a testis where the central cluster of cells (blue) is the niche (called a “hub”); the germline stem cells (GSCs) map to the first tier of (red) cells surrounding the niche, and these GSCs are intermingled with somatic stem cells (green), which express the somatic stem cell-specific factor Zfh-1. Another advantage to studying this system is that we can culture the testis and live-image the production of new stem cells (come see some gorgeous movies made by Gabby). And, excitingly, we have access to a testis single cell RNA sequence data set to help identify new regulators!

Building a Niche

Given that the niche is such a critical component regulating stem cell behavior, we also study how its cells are first specified, and how they assemble to form a functional niche. The photo shows a gonad with newly specified niche cells, marked by a cell surface protein (green). Again, combining genetics with lineage tracing and live-imaging we have uncovered several circuits necessary to specify these cells, and are studying how the individual cells migrate directionally and coalesce together to form the niche (come see some gorgeous movies made by Bailey!). We have recently learned that that coalescence involves cell biological and cell mechanical interactions between niche and stem cells.

The Hematopoietic Niche

Finally, we are extending our studies to the assembly of the insect hematopoietic niche, called the PSC (green cells). This niche controls the progenitors (magenta cells) for the innate immune system, and is comprised of a bilaterally-symmetric sets of cells specified in late-stage embryos. How these cells associate, migrate and coalesce to assume the final architecture for this niche is enirely unknown. Come see some gorgeous movies made by Kara showing how these cells migrate and coalesce to take up their final positions in the lymphatic organ. Kara is exploring how extracellular signals govern the precise positioning of this niche. The image is a snapshot from live-imaging, showing cells mid-way in their assembly as they 'zip up' to form the PSC niche, along with asociated heart cells and progenitors.

RECENT PUBLICATIONS

Anllo L, DiNardo S.: Visceral mesoderm signaling regulates assembly position and function of the Drosophila testis niche. Dev Cell 57: 1009-1023, Apr 2022.

Raz AA, Vida GS, Stern SR, Mahadevaraju S, Fingerhut JM, Viveiros JM, Pal S, Grey JR, Grace MR, Berry CW, Li H, Janssens J, Saelens W, Shao Z, Hu C, Yamashita YM, Przytycka T, Oliver B, Brill JA, Krause H, Matunis EL, White-Cooper H, DiNardo S, Fuller MT.: Emergent dynamics of adult stem cell lineages from single nucleus and single cell RNA-Seq of Drosophila testes. Elife 12: e82201, Feb 2023.

Lenhart Kari F, Capozzoli Benjamin, Warrick Gwen S D, DiNardo Stephen: Diminished Jak/STAT Signaling Causes Early-Onset Aging Defects in Stem Cell Cytokinesis. Current Biology : CB 29(2): 256-267.e3, Jan 2019.

Kari F. Lenhart Stephen DiNardo: Somatic cell encystment promotes abscission in germline stem cells following a regulated block in cytokinesis. Developmental Cell 34(2): 192-205, July 2015.

*Anllo Lauren, *Plasschaert Lindsey W, *Sui Justin, DiNardo Stephen: Live imaging reveals hub cell assembly and compaction dynamics during morphogenesis of the Drosophila testis niche. Developmental Biology 446(1): 102-118, 02 2019 Notes: * Co-First Authors.

Ong Katy, Collier Camille, DiNardo Stephen: Multiple feedback mechanisms fine-tune Rho signaling to regulate morphogenetic outcomes. Journal of Cell Science 132(8), Apr 2019.

Wingert L; DiNardo S. : Traffic jam functions in a branched pathway from Notch activation to niche cell fate. Development. Company of Biologists, 142(13): 2268-77, July 2015.

Ly Dan, Resch Erin, Ordiway George, DiNardo Stephen: Asymmetrically deployed actomyosin-based contractility generates a boundary between developing leg segments in Drosophila. Developmental biology 429(1): 165-176, 09 2017.

Donoughe, Seth. DiNardo, Stephen.: dachsous and frizzled contribute separately to planar polarity in the Drosophila ventral epidermis. Development 138(13): 2751-9, Jul 2011 Notes: Faculty of 1000 manuscript.

Leatherman, J. L., DiNardo, S.: Germline self-renewal requires cyst stem cells and stat regulates niche adhesion in Drosophila testes. Nat Cell Biol 12: 806–811, August 2010 Notes: COVER photo.

Leatherman, J. L., DiNardo, S.: Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal. Cell Stem Cell 3(1): 44-54, July 2008.

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