Article

Regulated -Cell Regeneration in the Adult Mouse Pancreas

Diabetes Center, University of California San Francisco, California, USA.
Diabetes (Impact Factor: 8.47). 05/2008; 57(4):958-66. DOI: 10.2337/db07-0913
Source: PubMed

ABSTRACT Several studies have shown that the adult pancreas possesses a limited potential for beta-cell regeneration upon tissue injury. One of the difficulties in studying beta-cell regeneration has been the lack of a robust, synchronized animal model system that would allow controlled regulation of beta-cell loss and subsequent proliferation in adult pancreas. Here we present a transgenic mouse regeneration model in which the c-Myc transcription factor/mutant estrogen receptor (cMycER(TAM)) fusion protein can be specifically activated in mature beta-cells. We have studied these transgenic mice by immunohistochemical and biochemical methods to assess the ablation and posterior regeneration of beta-cells. Activation of the cMycER(TAM) fusion protein results in synchronous and selective beta-cell apoptosis followed by the onset of acute diabetes. Inactivation of c-Myc leads to gradual regeneration of insulin-expressing cells and reversal of diabetes. Our results demonstrate that the mature pancreas has the ability to fully recover from almost complete ablation of all existing beta-cells. Our results also suggest the regeneration of beta-cells is mediated by replication of beta-cells rather than neogenesis from pancreatic ducts.

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Available from: David A Cano, Mar 20, 2015
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    • "For example, in rodents the β-cell replication rate is reported to be 2.5%, whereas in human it is only around 0.2% [65] [66]. Several studies have suggested that β-cells regenerate upon injury-driven tissue loss, but how and to what extent secreted molecules regulate this process is currently unknown [2] [66]. Betacellulin (BTC) was one of the first identified secreted proteins regulating β-cell proliferation. "
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    ABSTRACT: Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells resulting in failure of metabolic control. Even though type 1 and 2 diabetes differ in their pathogenesis, restoring β-cell function is the overarching goal for improved therapy of both diseases. This could be achieved either by cell-replacement therapy or by triggering intrinsic regenerative mechanisms of the pancreas. For type 1 diabetes, a combination of β-cell replacement and immunosuppressive therapy could be a curative treatment, whereas for type 2 diabetes enhancing endogenous mechanisms of β-cell regeneration might optimize blood glucose control. This review will briefly summarize recent efforts to allow β-cell regeneration where the most promising approaches are currently (1) increasing β-cell self-replication or neogenesis from ductal progenitors and (2) conversion of α-cells into β-cells.
    06/2014; 3(3):268-274. DOI:10.1016/j.molmet.2014.01.010
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    • "This is also true for beta-cell replenishment occurring in animals where c-myc conditional overexpression induced beta-cell apoptosis, and leading to diabetes. Following inactivation of c-myc overexpression insulin-producing cells regenerate and diabetes is reversed [114]. These studies are further sustained by the finding that, following partial pancreatectomy in mice, beta-cell regeneration occurs in the absence of the proendocrine marker Ngn3 reactivation [115]. "
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    ABSTRACT: The pancreas is composed of two compartments that deliver digestive enzymes and endocrine hormones to control the blood sugar level. The endocrine pancreas consists of functional units organized into cell clusters called islets of Langerhans where insulin-producing cells are found in the core and surrounded by glucagon-, somatostatin-, pancreatic polypeptide-, and ghrelin-producing cells. Diabetes is a devastating disease provoked by the depletion or malfunction of insulin-producing beta-cells in the endocrine pancreas. The side effects of diabetes are multiple, including cardiovascular, neuropathological, and kidney diseases. The analyses of transgenic and knockout mice gave major insights into the molecular mechanisms controlling endocrine pancreas genesis. Moreover, the study of animal models of pancreas injury revealed that the pancreas has the propensity to undergo regeneration and opened new avenues to develop novel therapeutic approaches for the treatment of diabetes. Thus, beside self-replication of preexisting insulin-producing cells, several potential cell sources in the adult pancreas were suggested to contribute to beta-cell regeneration, including acinar, intraislet, and duct epithelia. However, regeneration in the adult endocrine pancreas is still under controversial debate.
    12/2012; 2012(3):640956. DOI:10.5402/2012/640956
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    • "Myc activation in groups of MIG and MIGKO mice aged around 3 months old was induced by daily administration of 4-hydroxytamoxifen (4-OHT) or tamoxifen (Sigma) as previously described [27], [43]. Inactivation of c-MycERTAM protein was achieved following withdrawal of the drug [27]. "
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    ABSTRACT: The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II) plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration. We employed an in vivo model of 'switchable' c-Myc-induced beta cell ablation, pIns-c-MycER(TAM), in which 90% of beta cells are lost following 11 days of c-Myc (Myc) activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycER(TAM)/IGF-II(+/+) (MIG) mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycER(TAM)/IGF-II(+/-) (MIGKO) mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed. Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.
    PLoS ONE 09/2012; 7(9):e43623. DOI:10.1371/journal.pone.0043623 · 3.23 Impact Factor
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