In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes.
Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin(+) β-cells, glucagon(+) α-cells, and somatostatin(+) δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. DOI: http://dx.doi.org/10.7554/eLife.01846.001.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States.
Weida
W
Li
Mio
M
Nakanishi
Adrian
A
Zumsteg
Matthew
M
Shear
Christopher
C
Wright
Douglas A
DA
Melton
Qiao
Q
Zhou
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D019864:Somatostatin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097573:Red Fluorescent Protein
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D051473:Maf Transcription Factors, Large; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D000097573:Red Fluorescent Protein; C084010:pancreatic and duodenal homeobox 1 protein; C064658:RAG-1 protein
acinar to endocrine conversion; direct lineage conversion; in vivo reprogramming; islet delta, alpha, beta cells; pancreatic endocrine cells