Potential Pitfalls Of Stem Cellbased Therapies For Diabetes In Humans

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Both embryonic and adult stem cells represent an underdeveloped resource for the treatment and potential cure for a host of diseases, including type I diabetes. As efforts are made to develop transplantable tissue from each stem cell source, it is important to keep in mind potential pitfalls. Somatic stem cells, either from the bone marrow or ductal elements of the pancreas itself, could be obtained from a cadaver donor, related or unrelated live donor, or directly from the patient. In this final case, the need for immunosuppressive therapy to prevent graft rejection would be eliminated; however, autoimmune destruction of newly generated isogenic islet tissue would likely occur in the type I diabetic. Currently, the ability to expand ex vivo an islet progenitor cell population from ductal or discarded pancreatic tissue is quite limited, and a significant amount of scale-up would be required to make this a feasible therapeutic option. As with pancreas-derived stem cells, stem cells from bone marrow could be isolated from a number of different donors. These cells exhibit capacity for prolonged self-renewal in vitro, making them an attractive option. However, there are no data on the ex vivo differentiation of these cells to pancreas progenitors, and differentiation of these cells into islet-like cell types in vivo is a rare occurrence and may be dependent on acute injury. Much work must be carried out to develop protocols that allow the directed in vitro differentiation of bone marrow-derived stem cells or MAPCs to pancreatic islet lineages.

Embryonic stem cells have been shown to differentiate into various cell types, both in vitro and in vivo, including pancreatic islet lineages (39,49,98). However, functional islet tissue has not been derived from human ES cells to date, and whether ES cell-derived islet tissue will exhibit mature glucose-stimulated insulin secretion or immature function akin to fetal islets remains to be determined. Because theoretically there is no limit to the number of undifferentiated ES cells that can be grown in vitro, the amount of tissue for therapy generated from these cells is also potentially unlimited.

Recently, derivation of a human ES cell line derived from a blastocyst cloned using somatic cell nuclear transfer was reported (99), suggesting that it might some day be possible to grow tissues from isogenic cell lines from all prospective patients, though currently the extremely low efficiency of this process is prohibitive. Another option to prevent rejection without immunosuppressive therapy is to genetically engineer ES cells to be less immunogenic by adding immuno-modulatory genes, removing costimulatory molecules, or removing or altering non-self major histocompatibility complex proteins.

Protocols designed to prompt ES cells to differentiate into specific cell types en masse are required before these cells can be used in therapeutic settings. The tumorigenicity of ES cells is a potential caveat, even in situations where the vast majority of cultured cells undergo differentiation to the correct cell fate. While still in culture, genetic selection can be applied to ES cells both to increase the numbers of lineage-specific cell types (98,100-102) and to eliminate residual undifferentiated cells prior to transplantation (102).

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