Abstract

Understanding the function of lung progenitor cells is a critical to improve our fundamental understanding of lung development, but is also critical to design strategies aimed at improving lung regeneration or repair following injury. Recent evidence has demonstrated that significant functional and gene expression species- specific differences exist when comparing the developing human and mouse lung, suggesting that our fundamental understanding of human lung development is incomplete. This proposal will build on novel methods that allow us to isolate and propagate epithelial progenitor cells from developing human lungs in vitro, and novel methods to induce human lung epithelial progenitor cells from iPSCs in vitro. iPSC-derived lung progenitors are capable of long-term engraftment into the injured mouse airway where they differentiated multiple cell types within the adult murine lung. Through these studies, we have collectively defined an in vitro niche comprised of a minimal set of biochemical cues along with a physical environment (extracellular matrix) that supports lung epithelial progenitor cell growth in vitro. However, how niche factors functions to support lung epithelial progenitor maintenance and/or differentiation is unclear. This proposal will pursue aims that are designed to understand how specific niche factors mechanistically support epithelial progenitors in the developing human lung, and to interrogate the mechanisms by which human lung epithelial progenitor cells undergo cell fate specification.

Public Health Relevance

By using primary human tissue, human iPSCs and mouse models, this proposal will interrogate the mechanisms controlling epithelial progenitor cells and their subsequent differentiation into committed epithelial lineages. This work will lead to novel in vitro human model systems to study lung development and disease, will provide novel cell sources for regenerative medicine, and will inform novel therapeutic strategies to stimulate lung repair and regeneration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL119215-07
Application #
9770918
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2013-08-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Cruz-Acuña, Ricardo; Quirós, Miguel; Huang, Sha et al. (2018) Publisher Correction: PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery. Nat Protoc :
Miller, Alyssa J; Hill, David R; Nagy, Melinda S et al. (2018) In Vitro Induction and In Vivo Engraftment of Lung Bud Tip Progenitor Cells Derived from Human Pluripotent Stem Cells. Stem Cell Reports 10:101-119
Hrycaj, Steven M; Marty-Santos, Leilani; Cebrian, Cristina et al. (2018) Hox5 genes direct elastin network formation during alveologenesis by regulating myofibroblast adhesion. Proc Natl Acad Sci U S A 115:E10605-E10614
Miller, Alyssa J; Spence, Jason R (2017) In Vitro Models to Study Human Lung Development, Disease and Homeostasis. Physiology (Bethesda) 32:246-260
Cruz-Acuña, Ricardo; Quirós, Miguel; Farkas, Attila E et al. (2017) Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat Cell Biol 19:1326-1335
Ptaschinski, Catherine; Hrycaj, Steven M; Schaller, Matthew A et al. (2017) Hox5 Paralogous Genes Modulate Th2 Cell Function during Chronic Allergic Inflammation via Regulation of Gata3. J Immunol 199:501-509
Dye, Briana R; Miller, Alyssa J; Spence, Jason R (2016) How to Grow a Lung: Applying Principles of Developmental Biology to Generate Lung Lineages from Human Pluripotent Stem Cells. Curr Pathobiol Rep 4:47-57
Dye, Briana R; Dedhia, Priya H; Miller, Alyssa J et al. (2016) A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids. Elife 5:
Aurora, Megan; Spence, Jason R (2016) hPSC-derived lung and intestinal organoids as models of human fetal tissue. Dev Biol 420:230-238
Dye, Briana R; Hill, David R; Ferguson, Michael A H et al. (2015) In vitro generation of human pluripotent stem cell derived lung organoids. Elife 4:

Showing the most recent 10 out of 14 publications