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Colony-forming cells in the adult mouse pancreas are expandable in Matrigel and form endocrine/acinar colonies in laminin hydrogel

Jin, Liang and Feng, Tao and Shih, Hung Ping and Zerda, Ricardo and Luo, Angela and Hsu, Jasper and Mahdavi, Alborz and Sander, Maike and Tirrell, David A. and Riggs, Arthur D. and Ku, Hsun Teresa (2013) Colony-forming cells in the adult mouse pancreas are expandable in Matrigel and form endocrine/acinar colonies in laminin hydrogel. Proceedings of the National Academy of Sciences of the United States of America, 110 (10). pp. 3907-3912. ISSN 0027-8424. PMCID PMC3593860. doi:10.1073/pnas.1301889110.

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The study of hematopoietic colony-forming units using semisolid culture media has greatly advanced the knowledge of hematopoiesis. Here we report that similar methods can be used to study pancreatic colony-forming units. We have developed two pancreatic colony assays that enable quantitative and functional analyses of progenitor-like cells isolated from dissociated adult (2–4 mo old) murine pancreas. We find that a methylcellulose-based semisolid medium containing Matrigel allows growth of duct-like “Ring/Dense” colonies from a rare (∼1%) population of total pancreatic single cells. With the addition of roof plate-specific spondin 1, a wingless-int agonist, Ring/Dense colony-forming cells can be expanded more than 100,000-fold when serially dissociated and replated in the presence of Matrigel. When cells grown in Matrigel are then transferred to a Matrigel-free semisolid medium with a unique laminin-based hydrogel, some cells grow and differentiate into another type of colony, which we name “Endocrine/Acinar.” These Endocrine/Acinar colonies are comprised mostly of endocrine- and acinar-like cells, as ascertained by RNA expression analysis, immunohistochemistry, and electron microscopy. Most Endocrine/Acinar colonies contain beta-like cells that secrete insulin/C-peptide in response to D-glucose and theophylline. These results demonstrate robust self-renewal and differentiation of adult Ring/Dense colony-forming units in vitro and suggest an approach to producing beta-like cells for cell replacement of type 1 diabetes. The methods described, which include microfluidic expression analysis of single cells and colonies, should also advance study of pancreas development and pancreatic progenitor cells.

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URLURL TypeDescription DOIArticle CentralArticle
Mahdavi, Alborz0000-0002-8790-8112
Tirrell, David A.0000-0003-3175-4596
Additional Information:© 2013 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Arthur D. Riggs, January 29, 2013 (sent for review December 26, 2012). Published online before print February 19, 2013. We thank Lucy Brown, Alexander Spalla, and Pavinder Kaur from the Analytical Cytometry Core of City of Hope for assistance in flow sorting and Dr. Vincenzo Cirulli at the University of Washington for evaluating photomicrographs of electron microscopy. This work is supported in part by National Institutes of Health (NIH) Grant R01DK081587 (to H.T.K.), U01DK089533 (to A.D.R.), DK078803 (to M.S.), National Science Foundation NSF-DMR-1206121 (to D.A.T.), Office of Naval Research ONR-N00014-02-1 0958 and NSF-DBI-9970143 (to Electron Microscopy Core), NIH Grant P30 CA33572 (to Analytical Cytometry Core at City of Hope), a Juvenile Diabetes Research Foundation postdoctoral fellowship (to H.P.S.), and a City of Hope Eugene and Ruth Roberts Summer Student Academy fellowship (to A.L.). Author contributions: L.J. and H.T.K. designed research; L.J., T.F., H.P.S., R.Z., A.L., J.H., and H.T.K. performed research; H.P.S., A.M., M.S., and D.A.T. contributed new reagents/analytic tools; L.J., T.F., and H.P.S. analyzed data; and L.J., A.D.R., and H.T.K. wrote the paper.
Funding AgencyGrant Number
Office of Naval Research (ONR)N00014-02-1 0958
NIHP30 CA33572
Juvenile Diabetes Research FoundationUNSPECIFIED
City of Hope Eugene and Ruth Roberts Summer Student Academy fellowshipUNSPECIFIED
Subject Keywords:extracellular matrix proteins; Sry-related HMG box (Sox) 9; Promonin 1 (CD133); neurogenin 3; dickkopf1 (Dkk1)
Issue or Number:10
PubMed Central ID:PMC3593860
Record Number:CaltechAUTHORS:20130423-105847349
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:38078
Deposited On:23 Apr 2013 20:45
Last Modified:09 Nov 2021 23:33

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