De Novo Formation of Insulin-Producing "Neo-β Cell Islets" from Intestinal Crypts

Yi Ju Chen; Stacy R. Finkbeiner; Daniel Weinblatt; Matthew J. Emmett; Feven Tameire; Maryam Yousefi; Chenghua Yang; Rene Maehr; Qiao Zhou; Ruth Shemer; Yuval Dor; Changhong Li; Jason R. Spence; Ben Z. Stanger

doi:10.1016/j.celrep.2014.02.013

De Novo Formation of Insulin-Producing "Neo-β Cell Islets" from Intestinal Crypts

Yi Ju Chen, Stacy R. Finkbeiner, Daniel Weinblatt, Matthew J. Emmett, Feven Tameire, Maryam Yousefi, Chenghua Yang, Rene Maehr, Qiao Zhou, Ruth Shemer, Yuval Dor, Changhong Li, Jason R. Spence, Ben Z. Stanger^*

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

Abstract

The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an invivo screen by expressing three β cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia indiabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells. Ourresults thus demonstrate that the intestine is anaccessible and abundant source of functional insulin-producing cells.

Original language	English
Pages (from-to)	1046-1058
Number of pages	13
Journal	Cell Reports
Volume	6
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2014.02.013
State	Published - 27 Mar 2014

Bibliographical note

Funding Information:
We are grateful to Y. Dor, R. Stein, C. Lengner, K. Kaestner, K. Zaret, and Q.-C. Yu for helpful discussions; D. Melton for providing Ngn3CreER mice and R26Cherry mice; G. Gu for providing Ngn3 antibodies; and B. Madison for the Villin promoter fragment. We thank A. Stout and J. Zhao in the Penn Cell and Developmental Biology Microscopy Core for assistance with imaging, D. Williams and R. Meade for assistance with electron microscopy, and N. Tran and D. Sanchez for technical support. This work was supported by grants from NIH/NIDDK (R01-DK083355 and DP2-DK083111 to B.Z.S.; K01-DK091415 to J.R.S.; T32-DK094775 to S.R.F.), the Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), the Penn Institute for Diabetes Obesity and Metabolism, the University of Michigan Center for Organogenesis, the University of Michigan Biological Sciences Scholar Program, the Pew Charitable Trusts, and the Abramson Family Cancer Research Institute.

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10.1016/j.celrep.2014.02.013

Cite this

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title = "De Novo Formation of Insulin-Producing {"}Neo-β Cell Islets{"} from Intestinal Crypts",

abstract = "The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an invivo screen by expressing three β cell {"}reprogramming factors{"} in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into {"}neoislets{"} below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia indiabetic mice. Moreover, PMN expression in human intestinal {"}organoids{"} stimulates the conversion of intestinal epithelial cells into β-like cells. Ourresults thus demonstrate that the intestine is anaccessible and abundant source of functional insulin-producing cells.",

author = "Chen, {Yi Ju} and Finkbeiner, {Stacy R.} and Daniel Weinblatt and Emmett, {Matthew J.} and Feven Tameire and Maryam Yousefi and Chenghua Yang and Rene Maehr and Qiao Zhou and Ruth Shemer and Yuval Dor and Changhong Li and Spence, {Jason R.} and Stanger, {Ben Z.}",

note = "Funding Information: We are grateful to Y. Dor, R. Stein, C. Lengner, K. Kaestner, K. Zaret, and Q.-C. Yu for helpful discussions; D. Melton for providing Ngn3CreER mice and R26Cherry mice; G. Gu for providing Ngn3 antibodies; and B. Madison for the Villin promoter fragment. We thank A. Stout and J. Zhao in the Penn Cell and Developmental Biology Microscopy Core for assistance with imaging, D. Williams and R. Meade for assistance with electron microscopy, and N. Tran and D. Sanchez for technical support. This work was supported by grants from NIH/NIDDK (R01-DK083355 and DP2-DK083111 to B.Z.S.; K01-DK091415 to J.R.S.; T32-DK094775 to S.R.F.), the Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), the Penn Institute for Diabetes Obesity and Metabolism, the University of Michigan Center for Organogenesis, the University of Michigan Biological Sciences Scholar Program, the Pew Charitable Trusts, and the Abramson Family Cancer Research Institute. ",

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doi = "10.1016/j.celrep.2014.02.013",

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AU - Chen, Yi Ju

AU - Finkbeiner, Stacy R.

AU - Weinblatt, Daniel

AU - Emmett, Matthew J.

AU - Tameire, Feven

AU - Yousefi, Maryam

AU - Yang, Chenghua

AU - Maehr, Rene

AU - Zhou, Qiao

AU - Shemer, Ruth

AU - Dor, Yuval

AU - Li, Changhong

AU - Spence, Jason R.

AU - Stanger, Ben Z.

N1 - Funding Information: We are grateful to Y. Dor, R. Stein, C. Lengner, K. Kaestner, K. Zaret, and Q.-C. Yu for helpful discussions; D. Melton for providing Ngn3CreER mice and R26Cherry mice; G. Gu for providing Ngn3 antibodies; and B. Madison for the Villin promoter fragment. We thank A. Stout and J. Zhao in the Penn Cell and Developmental Biology Microscopy Core for assistance with imaging, D. Williams and R. Meade for assistance with electron microscopy, and N. Tran and D. Sanchez for technical support. This work was supported by grants from NIH/NIDDK (R01-DK083355 and DP2-DK083111 to B.Z.S.; K01-DK091415 to J.R.S.; T32-DK094775 to S.R.F.), the Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), the Penn Institute for Diabetes Obesity and Metabolism, the University of Michigan Center for Organogenesis, the University of Michigan Biological Sciences Scholar Program, the Pew Charitable Trusts, and the Abramson Family Cancer Research Institute.

PY - 2014/3/27

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N2 - The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an invivo screen by expressing three β cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia indiabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells. Ourresults thus demonstrate that the intestine is anaccessible and abundant source of functional insulin-producing cells.

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ER -

De Novo Formation of Insulin-Producing "Neo-β Cell Islets" from Intestinal Crypts

Abstract

Bibliographical note

UN SDGs

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