Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells.
Direct lineage conversion is a promising approach to generate therapeutically important cell types for disease modeling and tissue repair. However, the survival and function of lineage-reprogrammed cells in vivo over the long term has not been examined. Here, using an improved method for in vivo conversion of adult mouse pancreatic acinar cells toward beta cells, we show that induced beta cells persist for up to 13 months (the length of the experiment), form pancreatic islet-like structures and support normoglycemia in diabetic mice. Detailed molecular analyses of induced beta cells over 7 months reveal that global DNA methylation changes occur within 10 d, whereas the transcriptional network evolves over 2 months to resemble that of endogenous beta cells and remains stable thereafter. Progressive gain of beta-cell function occurs over 7 months, as measured by glucose-regulated insulin release and suppression of hyperglycemia. These studies demonstrate that lineage-reprogrammed cells persist for >1 year and undergo epigenetic, transcriptional, anatomical and functional development toward a beta-cell phenotype.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Weida
W
Li
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.
Claudia
C
Cavelti-Weder
Yingying
Y
Zhang
1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Yinying
Y
Zhang
1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Kendell
K
Clement
1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Scott
S
Donovan
Harvard Medical School, West Roxbury, Massachusetts, USA.
Gabriel
G
Gonzalez
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Center for System Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Jiang
J
Zhu
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.
Marianne
M
Stemann
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Ke
K
Xu
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Tatsu
T
Hashimoto
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.
Takatsugu
T
Yamada
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Mio
M
Nakanishi
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Yuemei
Y
Zhang
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Samuel
S
Zeng
Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
David
D
Gifford
1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Alexander
A
Meissner
Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.
Gordon
G
Weir
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Qiao
Q
Zhou
D061354:Acinar Cells / Q000166:cytology*; D000818:Animals; D001786:Blood Glucose; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D019175:DNA Methylation / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology*; D007515:Islets of Langerhans / Q000254:growth & development / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD
D001786:Blood Glucose