Long-term correction of hyperglycemia in diabetic mice after implantation of cultured human cells derived from fetal pancreas.
Type I diabetes is characterized by destruction of insulin-producing beta-islet cells in the pancreas resulting in hyperglycemia and associated morbidity. The successful treatment of diabetes by transplanted islets has resulted in renewed efforts to identify methods to augment islet availability. One approach is to identify and expand islet precursor cells able to later differentiate into functional endocrine cells. A population of cytokeratin 19-negative, vimentin-positive, insulin-negative, glucagon-negative, and nestin-positive cells was cultured from human fetal pancreas and passaged for over 20 population doublings. These cells were stimulated to form cell aggregates when grown on poly-D-lysine (PDL)-coated surfaces and then evaluated for differentiation potential using in vivo function as a surrogate marker for the presence of differentiated precursor cells. Streptozotocin-induced diabetic SCID mice implanted with PDL-induced cell aggregates were able to maintain glucose concentrations below 200 mg/dL for over 70 days (n = 5). In addition, human C-peptide was detectable in implanted animals but not in control animals. These findings show that a population of human fetal pancreas-derived cells (1) can be cultured and expanded in vitro, (2) can maintain the ability to differentiate into beta-islet-like cells, and (3) can correct hyperglycemia in a mouse model of diabetes. Further improvements in isolation, culture, and differentiation of human pancreas-derived beta-cell precursors may one day help to provide a novel source of islets for use in transplantation therapy to treat type I diabetes.
Wu
Fred
F
University of California, Davis Medical Center, UC Davis Cancer Center, Sacramento, California 95817, USA. fredwu@aya.yale.edu
Jagir
Michael
M
Powell
Jerry S
JS
D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D002469:Cell Separation; D002999:Clone Cells / Q000637:transplantation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000628:therapy*; D016332:Fetal Tissue Transplantation; D005934:Glucagon / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy*; D007328:Insulin / Q000032:analysis / Q000627:therapeutic use; D007381:Intermediate Filament Proteins / Q000032:analysis; D007515:Islets of Langerhans / Q000166:cytology*; D007633:Keratins / Q000032:analysis; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000032:analysis; D064231:Nestin; D010179:Pancreas / Q000166:cytology* / Q000196:embryology; D011107:Polylysine / Q000494:pharmacology; D033581:Stem Cell Transplantation / Q000379:methods; D013311:Streptozocin; D014183:Transplantation, Heterologous; D014746:Vimentin / Q000032:analysis
D015415:Biomarkers; D007328:Insulin; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D014746:Vimentin; D011107:Polylysine; D013311:Streptozocin; D007633:Keratins; D005934:Glucagon