Efficient generation of pancreatic beta cells from human embryonic stem cells

Efficient generation of pancreatic beta cells from human embryonic stem cells


More than 36 million people globally are affected by type 1 diabetes (T1D), a lifelong disorder where insulin producing cells are attacked and destroyed by the immune system resulting in deficient insulin production that requires daily blood glucose monitoring and administration of insulin. While successful outcomes from islet transplantations have been reported, very few patients can benefit from this therapeutic option due to limited access to cadaveric donor islets. Human pluripotent stem cell (hPSCs) could offer an unlimited and invariable source of insulin-producing beta cells for treatments of a larger population of T1D patients.

With the vision of providing a cell therapy for type 1 diabetes patients, scientists have identified a unique cell surface protein present on human pancreatic precursor cells providing for the first time a molecular handle to purify the cells whose fate is to become cells of the pancreas - including insulin producing cells. The work, outlined in a landmark study has been published in Cell Reports.

Comparative gene expression analysis revealed glycoprotein 2 (GP2) as a specific cell surface marker for isolating pancreatic endoderm cells (PECs) from differentiated hESCs and human fetal pancreas. Isolated GP2+ PECs efficiently differentiated into glucose responsive insulin-producing cells in vitro.

Authors found that in vitro PEC proliferation declines due to enhanced expression of the cyclin-dependent kinase (CDK) inhibitors CDKN1A and CDKN2A. However, they identified a time window when reducing CDKN1A or CDKN2A expression increased proliferation and yield of GP2+ PECs.

A biomarker to clearly separate cell populations is a holy grail of cell therapy research for the reasons of safety and end product consistency. By using this cell surface marker, the researchers have engineered a streamlined and simplified differentiation process to generate insulin-producing cells for future treatment of type 1 diabetes patients. The process enables cost-efficient manufacturing and exploits at its core an intermediate cell bank of purified pancreatic precursor cells.

The discovery of the new marker has also enabled the researchers to streamline and refine the process of producing hPSC-derived insulin cells.

"By starting with a purified population of pancreatic precursor cells instead of immature stem cells we eliminate the risk of having unwanted tumorigenic cells in the final cell preparation and thus generate a safer cell product for therapeutic purposes", explains first author on the paper.

Indeed, Semb's group is among the first to directly address not only the therapeutic concept but to incorporate very early the manufacturing considerations in their process to ensure that future commercialization will be possible.

http://danstem.ku.dk/news/towards-a-safe-and-scalable-cell-therapy-for-type-1-diabetes-by-simplifying-beta-cell-differentiation/

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