期刊
STEM CELLS TRANSLATIONAL MEDICINE
卷 4, 期 10, 页码 1214-1222出版社
WILEY
DOI: 10.5966/sctm.2015-0079
关键词
Embryonic stem cells; Insulin-secreting cells; Diabetes; Drug delivery systems; Cell therapy; Pancreas development
资金
- California Institute for Regenerative Medicine [SP1-06513]
- National Institute of Neurological Disorders and Stroke [NS047101]
The PEC-01 cell population, differentiated from human embryonic stem cells (hESCs), contains pancreatic progenitors (PPs) that, when loaded into macroencapsulation devices (to produce the VC-01 candidate product) and transplanted into mice, can mature into glucose-responsive insulin-secreting cells and other pancreatic endocrine cells involved in glucose metabolism. We modified the protocol for making PEC-01 cells such that 73%-80% of the cell population consisted of PDX1-positive (PDX1(+)) and NKX6.1(+) PPs. The PPs were further differentiated to islet-like cells (ICs) that reproducibly contained 73%-89% endocrine cells, of which approximately 40%-50% expressed insulin. A large fraction of these insulin-positive cells were single hormone-positive and expressed the transcription factors PDX1 and NKX6.1. To preclude a significant contribution of progenitors to the in vivo function of ICs, we used a simple enrichment process to remove remaining PPs, yielding aggregates that contained 93%-98% endocrine cells and 1%-3% progenitors. Enriched ICs, when encapsulated and implanted into mice, functioned similarly to the VC-01 candidate product, demonstrating conclusively that in vitro-produced hESC-derived insulin-producing cells can mature and function in vivo in devices. A scaled version of our suspension culture was used, and the endocrine aggregates could be cryo-preserved and retain functionality. Although ICs expressed multiple important (3 cell genes, the cells contained relatively low levels of several maturity-associated markers. Correlating with this, the time to function of ICs was similar to PEC-01 cells, indicating that ICs required cell-autonomous maturation after delivery in vivo, which would occur concurrently with graft integration into the host. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1214-1222
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