Abstract
Under normal conditions, the regeneration of mouse β cells is mainly dependent on their own duplication. Although there is evidence that pancreatic progenitor cells exist around duct, whether non-β cells in the islet could also potentially contribute to β cell regeneration in vivo is still controversial. Here, we developed a novel transgenic mouse model to study the pancreatic β cell regeneration, which could specifically inhibit β cell proliferation by overexpressing p21 cip in β cells via regulation of the Tet-on system. We discovered that p21 overexpression could inhibit β-cell duplication in the transgenic mice and these mice would gradually suffer from hyperglycemia. Importantly, the recovery efficiency of the p21-overexpressing mice from streptozotocin-induced diabetes was significantly higher than control mice, which is embodied by better physiological quality and earlier emergence of insulin expressing cells. Furthermore, in the islets of these streptozotocin-treated transgenic mice, we found a large population of proliferating cells which expressed pancreatic duodenal homeobox 1 (PDX1) but not markers of terminally differentiated cells. Transcription factors characteristic of early pancreatic development, such as Nkx2.2 and NeuroD1, and pancreatic progenitor markers, such as Ngn3 and c-Met, could also be detected in these islets. Thus, our work showed for the first time that when β cell self-duplication is repressed by p21 overexpression, the markers for embryonic pancreatic progenitor cells could be detected in islets, which might contribute to the recovery of these transgenic mice from streptozotocin-induced diabetes. These discoveries could be important for exploring new diabetes therapies that directly promote the regeneration of pancreatic progenitors to differentiate into islet β cells in vivo.
Highlights
For both type 1 and type 2 diabetes mellitus, one of the most critical pathogeneses is that the number of functional b cells is inadequate [1]
To study whether non-b cells in islets could be activated and contributed to b cell regeneration in some specific pathologic conditions such as b cell loss, we generated a double transgenic mouse model with the Tet-On system (Insulin-reverse tetracycline transactivator (rtTA)/TET-p21); the foreign gene p21 is controlled by the RIPII-rtTA promoter
In this transgenic mouse model, doxycycline treatment induces the specific overexpression of p21 in islet b cells (Fig. 1A), which can inhibit the proliferation of b cells, facilitating our study of the mechanism on b-cell regeneration in islets with pancreatic progenitor or precursor activation (Fig. 1B)
Summary
For both type 1 and type 2 diabetes mellitus, one of the most critical pathogeneses is that the number of functional b cells is inadequate [1]. To study the mechanisms underlying b-cell regeneration, several experimental models have been developed, including the chemical induction of diabetes [5], partial pancreatectomy [6], duct ligation or cellophane wrapping [7] and abnormal expression of destructive genes such as TGFa [8], diphtheria toxin A [9] and c-Myc [10]. It has been recently demonstrated with a unique mouse model of pancreatic damage (i.e., partial duct ligation), that the NGN3+ cells in duct lining could reappear in the adult pancreas following injury and differentiate into new b cells in transplanted mice [13] These two mechanisms (i.e., b-cell self-replication and reactivation of pancreatic progenitors) for b-cell regeneration have been demonstrated, there are still no direct evidences to indicate whether there are progenitor cells in islets, which could be reactivated for b-cell regeneration
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