Activation of ductal progenitor-like cells from adult human pancreas requires extracellular matrix protein signaling.

The adult human pancreas is an essential organ comprised of several cell types, and those of the pancreatic lineage include acinar, ductal, and islet cells. The acinar cells produce and secrete digestive enzymes (such as trypsin, elastase, and chymotrypsin) that are carried by the ductal cells to the common bile duct to assist with food digestion. The islet cells function to regulate blood sugar levels by secreting hormones (such as insulin and glucagon). One type of islet cell is the glucose-responsive, insulin-secreting beta cell, which decreases blood sugar levels after meals. In both type 1 and type 2 diabetes, these beta cells are either destroyed or become dysfunctional, making it necessary to monitor blood sugar levels and inject insulin when necessary. Recently, the FDA has approved allogeneic (or from another individual) islet cell transplantation to treat diabetes patients. Over the last twenty years, allogeneic islet cell transplantation has been shown to be an effective therapy to restore a patient’s ability to regulate their own blood sugar levels. However, a limited number of cadaveric donors has prompted many laboratories, including ours, to search for alternative sources of beta-like cells. We and others have shown that a small population of pancreatic ductal cells has the potential to form functional, beta-like cells. These rare ductal cells are termed progenitor-like cells, because they can self-renew (make more of themselves) and differentiate (make other, mature pancreatic cell types). Here, with support from CIRM, we delve further into understanding how specific environmental cues impact human ductal progenitor-like cell survival and activation. First, we identified the minimal factors necessary to promote human ductal progenitor-like cell survival and growth, which include 6 chemically defined growth factors and a protein product from a murine cell line. Second, we discovered that the protein product from the abovementioned murine cell line is required to activate ductal progenitor-like cells. This imposes a problem for future clinical application because a murine cell line derived product has safety concern for human use. Therefore, the third aspect of our study was to identify human proteins that can replace the murine cell line derived product. We found human collagen IV as a key factor that promotes survival and activation of ductal progenitor-like cells. Additionally, we confirmed molecular mechanism of collagen IV, and showed that one of the main receptors of collagen IV, known as the integrin receptor α1β1, is required for the pro-survival and activation effects of collagen IV. Overall, our studies contribute to the field of regenerative medicine aimed at restoring functional islet cells to diabetes patients who have lost the ability to regulate their own blood sugar levels. We add mechanistic insight into how the environment signals activate a rare population of ductal progenitor-like cells, which can improve clinical translation of these cells for therapeutic purposes.