A small molecule that directs differentiation of human ESCs into the pancreatic lineage.
Stepwise differentiation from embryonic stem cells (ESCs) to functional insulin-secreting beta cells will identify key steps in beta-cell development and may yet prove useful for transplantation therapy for diabetics. An essential step in this schema is the generation of pancreatic progenitors--cells that express Pdx1 and produce all the cell types of the pancreas. High-content chemical screening identified a small molecule, (-)-indolactam V, that induces differentiation of a substantial number of Pdx1-expressing cells from human ESCs. The Pdx1-expressing cells express other pancreatic markers and contribute to endocrine, exocrine and duct cells, in vitro and in vivo. Further analyses showed that (-)-indolactam V works specifically at one stage of pancreatic development, inducing pancreatic progenitors from definitive endoderm. This study describes a chemical screening platform to investigate human ESC differentiation and demonstrates the generation of a cell population that is a key milepost on the path to making beta cells.
Chen
Shuibing
S
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
Borowiak
Malgorzata
M
Fox
Julia L
JL
Maehr
René
R
Osafune
Kenji
K
Davidow
Lance
L
Lam
Kelvin
K
Peng
Lee F
LF
Schreiber
Stuart L
SL
Rubin
Lee L
LL
Melton
Douglas
D
D000818:Animals; D015415:Biomarkers; D002273:Carcinogens / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007769:Lactams / Q000494:pharmacology*; D051379:Mice; D015534:Trans-Activators / Q000378:metabolism
D015415:Biomarkers; D002273:Carcinogens; D018398:Homeodomain Proteins; D007211:Indoles; D007769:Lactams; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C043969:indolactam V