Signals from the embryonic mouse pancreas induce differentiation of human embryonic stem cells into insulin-producing beta-cell-like cells.
The recent success in restoring normoglycemia in type 1 diabetes by islet cell transplantation indicates that cell replacement therapy of this severe disease is achievable. However, the severe lack of donor islets has increased the demand for alternative sources of beta-cells, such as adult and embryonic stem cells. Here, we investigate the potential of human embryonic stem cells (hESCs) to differentiate into beta-cells. Spontaneous differentiation of hESCs under two-dimensional growth conditions resulted in differentiation of Pdx1(+)/Foxa2(+) pancreatic progenitors and Pdx1(+)/Isl1(+) endocrine progenitors but no insulin-producing cells. However, cotransplantation of differentiated hESCs with the dorsal pancreas, but not with the liver or telencephalon, from mouse embryos resulted in differentiation of beta-cell-like cell clusters. Comparative analysis of the basic characteristics of hESC-derived insulin(+) cell clusters with human adult islets demonstrated that the insulin(+) cells share important features with normal beta-cells, such as synthesis (proinsulin) and processing (C-peptide) of insulin and nuclear localization of key beta-cell transcription factors, including Foxa2, Pdx1, and Isl1.
Brolén
Gabriella K C
GK
Division of Developmental Biology, Department of Experimental Medical Science, Lund University, B10 SE-22184 Lund, Sweden.
Heins
Nico
N
Edsbagge
Josefina
J
Semb
Henrik
H
D000818:Animals; D002096:C-Peptide / Q000032:analysis / Q000097:blood; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology*; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis / Q000096:biosynthesis*; D007515:Islets of Langerhans / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology*; D015534:Trans-Activators / Q000032:analysis
D002096:C-Peptide; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C485184:enhanced green fluorescent protein; C084010:pancreatic and duodenal homeobox 1 protein; D049452:Green Fluorescent Proteins