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Colony-Forming Progenitor Cells in the Postnatal Mouse Liver and Pancreas Give Rise to Morphologically Distinct Insulin-Expressing Colonies in 3D Cultures

Jin, Liang and Feng, Tao and Chai, Jing and Ghazalli, Nadiah and Gao, Dan and Zerda, Ricardo and Li, Zhuo and Hsu, Jasper and Mahdavi, Alborz and Tirrell, David A. and Riggs, Arthur D. and Ku, Hsun Teresa (2014) Colony-Forming Progenitor Cells in the Postnatal Mouse Liver and Pancreas Give Rise to Morphologically Distinct Insulin-Expressing Colonies in 3D Cultures. Review of Diabetic Studies, 11 (1). pp. 35-50. ISSN 1613-6071. PMCID PMC4295799. https://resolver.caltech.edu/CaltechAUTHORS:20141222-133544740

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Abstract

In our previous studies, colony-forming progenitor cells isolated from murine embryonic stem cell-derived cultures were differentiated into morphologically distinct insulin-expressing colonies. These colonies were small and not light-reflective when observed by phase-contrast microscopy (therefore termed “Dark” colonies). A single progenitor cell capable of giving rise to a Dark colony was termed a Dark colony-forming unit (CFU-Dark). The goal of the current study was to test whether endogenous pancreas, and its developmentally related liver, harbored CFU-Dark. Here we show that dissociated single cells from liver and pancreas of one-week-old mice give rise to Dark colonies in methylcellulose-based semisolid culture media containing either Matrigel or laminin hydrogel (an artificial extracellular matrix protein). CFU-Dark comprise approximately 0.1% and 0.03% of the postnatal hepatic and pancreatic cells, respectively. Adult liver also contains CFU-Dark, but at a much lower frequency (~0.003%). Microfluidic qRT-PCR, immunostaining, and electron microscopy analyses of individually handpicked colonies reveal the expression of insulin in many, but not all, Dark colonies. Most pancreatic insulin-positive Dark colonies also express glucagon, whereas liver colonies do not. Liver CFU-Dark require Matrigel, but not laminin hydrogel, to become insulin-positive. In contrast, laminin hydrogel is sufficient to support the development of pancreatic Dark colonies that express insulin. Postnatal liver CFU-Dark display a cell surface marker CD133^(+)CD49f^(low)CD107b^(low) phenotype, while pancreatic CFU-Dark are CD133^-. Together, these results demonstrate that specific progenitor cells in the postnatal liver and pancreas are capable of developing into insulin-expressing colonies, but they differ in frequency, marker expression, and matrix protein requirements for growth.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1900/RDS.2014.11.35DOIArticle
http://www.soc-bdr.org/content/e4/articlelookup?showfulltext=1&volume=11&firstpage=35PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295799/PubMed CentralArticle
ORCID:
AuthorORCID
Mahdavi, Alborz0000-0002-8790-8112
Tirrell, David A.0000-0003-3175-4596
Additional Information:Copyright © by Lab & Life Press/SBDR Manuscript submitted February 15, 2013; resubmitted June 20, 2013; accepted July 9, 2013. We thank Lucy Brown and Alexander Spalla from the Analytical Cytometry Core of City of Hope for assistance in flow sorting. This work is supported in part by National Institutes of Health (NIH) grants R01DK081587 and R01DK099734 to H.T.K., U01DK089533 to A.D.R., National Science Foundation NSF-DMR-1206121 and California Institute for Regenerative Medicine grant RB5-07398 to D.A.T., and NIH P30CA33572 to Analytical Cytometry Core at City of Hope. We also gratefully acknowledge support from Ella Fitzgerald Charitable Foundation, John C. Hench Foundation, Gordon Ross Medical Foundation, and Oxnard Foundation. This work is supported in part by National Institutes of Health (NIH) grants R01DK081587 and R01DK099734 to H.T.K., U01DK089533 to A.D.R., and P30 CA33572 to the Analytical Cytometry Core at City of Hope, and by National Science Foundation grant DMR-1206121 and California Institute for Regenerative Medicine grant RB5-07398 to D.A.T.
Funders:
Funding AgencyGrant Number
NIHR01DK081587
NIHR01DK099734
NIHU01DK089533
NSFDMR-1206121
California Institute for Regenerative Medicine (CIRM)RB5-07398
NIHP30 CA33572
Ella Fitzgerald Charitable FoundationUNSPECIFIED
John C. Hench FoundationUNSPECIFIED
Gordon Ross Medical FoundationUNSPECIFIED
Oxnard FoundationUNSPECIFIED
Issue or Number:1
PubMed Central ID:PMC4295799
Record Number:CaltechAUTHORS:20141222-133544740
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141222-133544740
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:52627
Collection:CaltechAUTHORS
Deposited By: Anne Hormann
Deposited On:22 Dec 2014 21:36
Last Modified:03 Oct 2019 07:44

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