Rebecca A. Wingert Elizabeth and Michael Gallagher Associate Professor

Stem Cells in Renal System Development and Regeneration
Rebecca A.  Wingert

Research Interests:

The Wingert Lab studies the genetic and molecular mechanisms that control how renal stem cells accomplish kidney formation, impact kidney homeostasis, and facilitate kidney regeneration following organ injury. Understanding these processes has broad implications for identifying the basis of renal birth defects and the responses to tissue damage that lead to kidney disease. Kidney diseases are a growing global healthcare issue: they affect epidemic numbers of children and adults worldwide, and are steadily climbing in incidence. Kidney diseases can be treated with renal replacement through dialysis or organ transplant, but both strategies require life-long medical management and can involve significant complications. Knowledge obtained from studying the basic biology of the renal system can provide a valuable way to discover innovative therapies for kidney disorders.

Research in the Wingert Lab centers around two major areas:

  1. Kidney Development Research: How do renal stem cells arise during development? How are nephrons constructed from renal stem/progenitor precursors? We are seeking to identify the genetic requirements for making renal cells. We utilize classical forward genetic screening and chemical genetics to study the molecules that affect in nephron formation. One benefit of these integrated approaches is that we can discover essential genes and signaling pathways that have never been implicated in renal progenitor biology. In addition, we perform expression studies to identify factors expressed by kidney cells during nephrogenesis, then assign their functional roles using reverse genetics, including knockdown and genome targeting strategies, as well as overexpression techniques to examine gain-of-function.
  2. Kidney Regeneration and Aging Research: How can damaged nephron components be replaced? Are there renal stem cells that can facilitate treatment of renal diseases? Can differentiated nephron cells be induced to regenerate damaged nephrons? Can the activation of kidney developmental pathways facilitate regeneration? How does the kidney age, and is the aging of renal stem cells a contributing factor to the incidence of kidney disease? We are using models of nephron injury in the embryo and adult zebrafish to discover the cell and molecular events that are required for nephron regeneration during the lifetime of the animal. Along with our nephron development studies, it is our hope that these lines of inquiry will shed novel insights into the activities of kidney cells and guide the creation of new therapeutics.

While kidney diseases are diverse in origin, many share a common aspect: alterations to the basic unit of the kidney called the nephron. Each nephron is an epithelial tube that is highly specialized to excrete metabolic waste. Nephrons contain a blood filter that collects fluid from the circulation and a long tubule that consists of a series of segments with different epithelial cell types. Nephron segments perform discrete tasks in modifying the filtrate by reabsorbing and secreting solutes—jobs that enable the retention of desirable nutrients and export of metabolic wastes. Human kidneys are architecturally complex because they contain many nephrons (ranging from several hundred thousand to over one million) that have intricate loops and convolutions, and are organized in arbor-like arrays. The signaling pathways that control how renal stem cells give rise to nephrons during kidney development are poorly understood. Part of the reason for this is that the architecture and internal location of the kidney pose challenges for studying nephron development and dysfunction in mammals. For some time, there has been experimental evidence that the kidney exhibits a limited capacity to regenerate. Damage to epithelial cells in nephrons can be followed by a local regenerative response in which new nephron epithelial cells are made. However, the molecular mechanisms that enable this type of nephron regeneration remain largely enigmatic, and their discovery is hampered by the aforementioned limitations of existing mammalian models.

To study how nephrons are made during development and regeneration, we use the zebrafish, Danio rerio. The zebrafish is an outstanding model for kidney research for numerous reasons. First, zebrafish are a vertebrate species and share many similarities with more complex vertebrates like mammals. For example, there is a high degree of conservation between gene function and basic cellular processes between zebrafish and mammals. Zebrafish embryos develop outside the mother and are optically transparent, enabling the direct visualization of organ development. The embryo forms an anatomically simple kidney that is made up of two nephrons, while the zebrafish adult kidney displays complex nephron arrangements analogous to other higher vertebrates. Zebrafish nephrons are comprised of segments with epithelial cells that share gene expression signatures and ultrastructural traits with the segments that typify vertebrate nephrons. Importantly, there is a diverse arsenal of molecular tools now available to the zebrafish researcher, and these enable high-resolution study of cell biology and genetic analysis.

 

Biography:

  • Chair, Institutional Animal Care and Use Committee, 2017-Present
  • Director of Graduate Studies, Department of Biological Sciences, Notre Dame 2016–Present
  • Associate Professor, Department of Biological Sciences, Notre Dame 2016–Present
  • Stem Cell and Regenerative Medicine Center, Faculty 2015–Present
  • Association for Women in Science (AWIS), Notre Dame Chapter, Faculty Advisor 2013–Present
  • Gallagher Family Professorship in Stem Cell Biology 2012–Present
  • Integrated Biomedical Sciences (IBMS) Graduate Program, Faculty 2012–Present
  • Chemistry–Biochemistry–Biology–Interface (CBBI), Faculty 2011–Present
  • National Science Foundation Summer Research Experiences for Undergraduates (NSF REU), Biological Sciences at University of Notre Dame, Faculty 2010–Present
  • Assistant Professor, Department of Biological Sciences, Notre Dame 2010–2016
  • Harvard Stem Cell Institute, Affiliated Faculty 2008–2010
  • Board of Tutors in Biochemical Sciences, Harvard University 2008–2010
  • Instructor in Medicine, Harvard Medical School 2007–2010
  • Continuing Education/Special Programs Instructor, Harvard University 2003–2007
  • Postdoctoral Fellow, Harvard Medical School and Massachusetts General Hospital 2005–2010
  • Ph.D. Cell and Developmental Biology, Harvard University 1999–2005
  • B.A. English, B.S. Biology, Muhlenberg College 1995–1999

 

Recent Papers:

  • Drummond BE, Wingert RA. 2018. Scaling up to study brca2: the zeppelin zebrafish mutant reveals a role for brca2 in embryonic development of kidney mesoderm. Can Cell Microenviron 5: e1630. DOI: 10.14800/ccm.1630
  • Marra AN, White A, Ulrich M, Springer M, Wingert RA. 2017. Visualizing multiciliated cells in the zebrafish through a combined protocol of whole mount fluorescent in situ hybridization and immunofluorescence. J Vis Exp Nov 18; (129), e56261. DOI: 10.3791/56261
  • Kroeger Jr PT, Drummond BE, Miceli R, McKernan M, Gerlach GF, Marra AN, Fox A, McCampbell KK, Leshchiner I, Rodriguez-Mari A, Bremiller R, Thummel R, Davidson AJ, Postlethwait J, Goessling W, Wingert RA. 2017. The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. Dev Biol 428(1): 148-163. DOI: 10.1016/j.ydbio.2017.05.025
  • Chambers BE, Wingert RA. 2017. Principles of stem cell biology applied to the kidney. Kidney Transplantation, Bioengineering & Regeneration Editors: Orlando G., Remuzzi G., Williams D.F. Elsevier Press.
  • Drummond BE, Li Y, Marra AN, Cheng CN, Wingert RA. 2017. Interplay between the tbx2a/b transcription factors and Notch signaling directs nephron segmentation and corpuscles of Stannius formation in zebrafish. Dev Biol 421(1): 52-66. DOI: 10.1016/j.ydbio.2016.10.019
  • Morales EE, Wingert RA. 2017. Zebrafish as a kidney disease model. Results Probl Cell Differ 60: 55-75. Special issue entitled: “Kidney Development and Disease” DOI: 10.1007/978-3-319-51436-9_3.
  • Poureetezadi SJ, Cheng CN, Chambers JM, Drummond BE, Wingert RA. 2016. Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development. eLife pii: e17551. DOI: 10.7554/eLife.17551
  • Poureetezadi SJ, Wingert RA. 2016. Little fish, big catch: zebrafish as a model of kidney disease. Kidney Int 89(6): 1204-1210. DOI: 10.1016/j.kint.2016.01.031
  • Chambers BE, Wingert RA. 2016. Renal progenitors: roles in kidney disease and regeneration. World J Stem Cells 8(11): 367-375. DOI: 10.4252/wjsc.v8.i11.367
  • McKee RA , Wingert RA. 2016. Nephrotoxin microinjection in zebrafish to model acute kidney injury. J Vis Exp Jul 17;(113). DOI: 10.3791/54241
  • Marra A, Li Y, Wingert RA. 2016. Antennas of organ morphogenesis: the roles of cilia in vertebrate kidney development. Genesis 54: 457-469 DOI: 10.1002/dvg22957
  • Chambers JM, McKee RA, Drummond BD, Wingert RA. 2016. Evolving technology: creating kidney organoids from stem cells. AIMS Bioengineering 3(3): 305-318. DOI: 10.3934/bioeng.2016.3.305
  • Marra A, Wingert RA. 2016. Epithelial cell fate in the nephron tubule is mediated by the ETS transcription factors etv5a and etv4 during zebrafish kidney development. Dev Biol 411(2): 231-245.DOI: 0.1016/j.ydbio.2016.01.035
  • McKee RA, Wingert RA. 2016. Repopulating decellularized kidney scaffolds: an avenue for ex vivo organ generation. Materials 9(3) pii: 190. DOI: 10.3390/ma9030190
  • Drummond BE, Wingert RA. 2016. Insights into kidney stem cell development using zebrafish. World J Stem Cells 8(2): 22-31. DOI: 10.4252/wjsc.v8.i2.22