Stem cells regenerate tissue by dividing asymmetrically, producing more stem cells (self- renewal) as well as differentiating daughters. Although differentiation is usually considered irreversible, there is increasing evidence that the rules of irreversibility can be broken following injury or in cell culture. The conversion of a differentiated cell to a less differentiated cell type, or dedifferentiation, endows certain organisms with remarkable regenerative properties. Similarly, cells of one type can often be induced to adopt a new fate even that of another lineage, in a process called transdifferentiation. Despite centuries of investigation, however, dedifferentiation and transdifferentiation are poorly understood at the molecular level, particularly in situations where they occur in intact tissues. We use Drosophila spermatogenesis as a model stem cell system, since it parallels mammalian spermatogenesis, yet we can precisely locate the sperm-producing spermatogonial (or germ line stem cells, GSCs) and manipulate their microenvironment (niche) genetically. In this niche, local cytokine and TGF-beta signaling promotes stem cell renewal, while cells leaving the niche differentiate. By manipulating GSC maintenance genetically in vivo we have discovered a surprising degree of plasticity in this lineage;differentiating spermatogonia can reverse their path and dedifferentiate into GSCs. Additional forms of damage also trigger novel mechanisms of stem cell regeneration in this tissue. Since cell fate transformation (or plasticity) may be a general feature of many stem cell systems, but is often difficult to study in intact tissues, we propose to use the powerful tools of Drosophila genetics to study these events. This work will begin to reveal the molecular mechanisms by which differentiating cells can be coaxed to reverse their path and become functional stem cells. This will advance the field of regenerative medicine and also further our understanding of spermatogonial stem cell renewal, a fundamental aspect of male reproduction.

Public Health Relevance

This work will contribute significantly to what is known about the mechanisms that regulate the generation of new stem cells within an intact stem cell microenvironment (or niche) in a living organism under both normal conditions and after tissue damage. Understanding how signals within a tissue promote the formation of stem cells from other types of cells is of fundamental importance for developing successful strategies to effectively promote tissue regeneration in living organisms.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052937-08
Application #
8600180
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Moss, Stuart B
Project Start
2007-03-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
8
Fiscal Year
2014
Total Cost
$306,270
Indirect Cost
$119,520
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ma, Qing; Wawersik, Matthew; Matunis, Erika L (2014) The Jak-STAT target Chinmo prevents sex transformation of adult stem cells in the Drosophila testis niche. Dev Cell 31:474-86
Hétié, Phylis; de Cuevas, Margaret; Matunis, Erika (2014) Conversion of quiescent niche cells to somatic stem cells causes ectopic niche formation in the Drosophila testis. Cell Rep 7:715-21
Stine, Rachel R; Matunis, Erika L (2013) Stem cell competition: finding balance in the niche. Trends Cell Biol 23:357-64
Sheng, X Rebecca; Brawley, Crista M; Matunis, Erika L (2009) Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis. Cell Stem Cell 5:191-203