title: Reversal of hyperglycemia by insulin-secreting rat bone marrow- and blastocyst-derived hypoblast stem cell-like cells.
abstract: β-cell replacement may efficiently cure type 1 diabetic (T1D) patients whose insulin-secreting β-cells have been selectively destroyed by autoantigen-reactive T cells. To generate insulin-secreting cells we used two cell sources: rat multipotent adult progenitor cells (rMAPC) and the highly similar rat extra-embryonic endoderm precursor (rXEN-P) cells isolated under rMAPC conditions from blastocysts (rHypoSC). rMAPC/rHypoSC were sequentially committed to definitive endoderm, pancreatic endoderm, and β-cell like cells. On day 21, 20% of rMAPC/rHypoSC progeny expressed Pdx1 and C-peptide. rMAPCr/HypoSC progeny secreted C-peptide under the stimulus of insulin agonist carbachol, and was inhibited by the L-type voltage-dependent calcium channel blocker nifedipine. When rMAPC or rHypoSC differentiated d21 progeny were grafted under the kidney capsule of streptozotocin-induced diabetic nude mice, hyperglycemia reversed after 4 weeks in 6/10 rMAPC- and 5/10 rHypoSC-transplanted mice. Hyperglycemia recurred within 24 hours of graft removal and the histological analysis of the retrieved grafts revealed presence of Pdx1-, Nkx6.1- and C-peptide-positive cells. The ability of both rMAPC and HypoSC to differentiate to functional β-cell like cells may serve to gain insight into signals that govern β-cell differentiation and aid in developing culture systems to commit other (pluripotent) stem cells to clinically useful β-cells for cell therapy of T1D.
authors.affiliation: Stamcel Instituut Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Anujith
authors.initials: A
authors.lastname: Kumar
authors.forename: Antonio
authors.initials: A
authors.lastname: Lo Nigro
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.forename: Qing
authors.initials: Q
authors.lastname: Cai
authors.forename: Camila
authors.initials: C
authors.lastname: Esguerra
authors.forename: Molly
authors.initials: M
authors.lastname: Nelson-Holte
authors.forename: Yves
authors.initials: Y
authors.lastname: Heremans
authors.forename: María
authors.initials: M
authors.lastname: Jiménez-González
authors.forename: Angelo
authors.initials: A
authors.lastname: Porciuncula
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Bert
authors.initials: B
authors.lastname: Binas
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hering
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
authors.forename: Miguel
authors.initials: M
authors.lastname: Barajas
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology* / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002096:C-Peptide / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000601:surgery; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000601:surgery; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000637:transplantation; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D005855:Germ Layers / Q000378:metabolism / Q000637:transplantation*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000601:surgery*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000637:transplantation; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D002096:C-Peptide; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein