Pancreatic stem cells

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Endocrine pancreas, as well as the nervous system and heart, are organs with a very limited proliferative capacity compared to epidermis of the skin, intestinal epithelium, muscle, liver (after hepatectomy) and the very well studied bone marrow tissue (responsible for blood cell generation and osteoarticular turnover). Nevertheless, an interesting finding is that the tissues with no proliferation, such as the nervous system, bear progenitor stem cells. This is a key finding, because the replication and differentiation of these cells could be stimulated in vivo or in vitro prior to recipient implantation. Unfortunately, the presence of stem cells in pancreatic tissue still remains an elusive question.

Several reports indicate that islet neogenesis from pancreatic duct cells play an important role in the recovery of endocrine mass after partial pan-createctomy. Furthermore, islet-like cell structures or cultivated human islets buds (CHIBs) have been obtained from the density gradient fraction rich in duct cells during islets fractionation.49 To achieve this, cells need to be expanded in serum free ITS medium (insulin + transferrin + selenium) containing nicotinamide and keratinocyte growth factor. After several days of culture, confluent cells were overlayed with Matrigel, which favors the formation of tridimensional structures positive for insulin and glucagon. However, the amount of insulin produced and the |-cell mass obtained are still very low for transplantation protocols, suggesting the need to search for protocols to promote cell expansion and enrich the hormone content.

These data seem to favor the existence of a progenitor or stem-like cell in the pancreas, located in ducts that can be bioengineered in vitro to produce insulin-positive cells. If these cells are implicated in vivo in the endocrine pancreas, turnover is still a matter of debate. In this context, Melton has provided evidence that new |-cells arise from replication of pre-existing differentiated | -cells, questioning the existence of a stem cell population in pancreatic tissue.50 The experimental design is based on genetic lineage tracing of insulin gene expression cells. It is difficult to argue against the rationale and results of these elegant experiments. Even more interesting, when the same gradient density fraction was devoid from pancreatic |-cells by exposure to alloxan or streptozotocin (that selectively attack insulin-producing cells) no CHIBs were obtained (unpublished results by several groups, including ours).

Since regeneration depends on the size of the insult, it may be concluded that |-cell replication does not exclude islet neogenesis in the rodent after subtotal pancreatectomy (90% removal) or the participation of pancreatic progenitors from islets, provided that those unipotent progenitors are capable of expressing insulin. In addition, it is still unknown if the endocrine pancreatic stem cells respond equally to different stimuli, including mechanical (i.e. pancreatectomy) or chemical (i.e. streptozotocin administration) insults. Altogether, the data indicate that complementary approaches should be adopted to address this relevant question for pancreas regeneration.

Therefore, the main conclusion from all these studies is that the potential pancreatic stem cell has not been isolated nor identified so far. Some laboratories are claiming that nestin-positive cells within the duct could be this potential cell. But nestin is a protein of intermediary filaments present in neurons derived from the ectoderm, while endocrine pancreatic cells are derived from the endoderm. In addition, recent evidence supports the participation of nestin-positive cells in vascular intra-islet structures.14

Demonstration and subsequent characterization of the putative pancreatic stem-progenitor cell would be a key finding in the field, opening new possibilities for autotransplantation. Replacement protocols using pancreas from cadaveric donors would require the setting up of in vitro expansion and differentiation protocols. In addition, increasing the insulin production of ductal tissue opens new possibilities on the use of cadaveric pancreatic tissue, autotransplantation and pancreas regeneration. However, more research is required to exploit this area.

Although very preliminary, the possibility of using de-differentiated exocrine tissue to obtain islet-like structures has been suggested. Under certain circumstances exocrine tissue may transdifferentiate into liver tissue, a close derivative of the endoderm. The proposal would be that exocrine tissue may lose the differentiation stage to a progenitor that may be further engineered to endocrine tissue.

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