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Stem Cell Reports. 2017 Dec 12;9(6):1780-1795. doi: 10.1016/j.stemcr.2017.10.022. Epub 2017 Nov 30.

Generation of Induced Progenitor-like Cells from Mature Epithelial Cells Using Interrupted Reprogramming.

Author information

1
Division of Thoracic Surgery, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada.
2
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada.
3
Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
4
Programme in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
5
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
6
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3H7, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5S 1A1, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada. Electronic address: nagy@lunenfeld.ca.
7
Division of Thoracic Surgery, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address: tom.waddell@uhn.ca.

Abstract

A suitable source of progenitor cells is required to attenuate disease or affect cure. We present an "interrupted reprogramming" strategy to generate "induced progenitor-like (iPL) cells" using carefully timed expression of induced pluripotent stem cell reprogramming factors (Oct4, Sox2, Klf4, and c-Myc; OSKM) from non-proliferative Club cells. Interrupted reprogramming allowed controlled expansion yet preservation of lineage commitment. Under clonogenic conditions, iPL cells expanded and functioned as a bronchiolar progenitor-like population to generate mature Club cells, mucin-producing goblet cells, and cystic fibrosis transmembrane conductance regulator (CFTR)-expressing ciliated epithelium. In vivo, iPL cells can repopulate CFTR-deficient epithelium. This interrupted reprogramming process could be metronomically applied to achieve controlled progenitor-like proliferation. By carefully controlling the duration of expression of OSKM, iPL cells do not become pluripotent, and they maintain their memory of origin and retain their ability to efficiently return to their original phenotype. A generic technique to produce highly specified populations may have significant implications for regenerative medicine.

KEYWORDS:

generation of induced progenitor-like cells

PMID:
29198829
PMCID:
PMC5785620
DOI:
10.1016/j.stemcr.2017.10.022
[Indexed for MEDLINE]
Free PMC Article

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