Streptozotocin-induced partial beta cell depletion in nude mice without hyperglycaemia induces pancreatic morphogenesis in transplanted embryonic stem cells

Abstract

Aims/hypothesis It appears that the adult pancreas has limited regenerative ability following beta cell destruction by streptozotocin (STZ). However, it is not clear if this limitation is due to an inability to respond to, rather than an absence of, regenerative stimuli. In this study we aimed to uncouple the regenerative signal from the regenerative response by using an exogenous stem cell source to detect regenerative stimuli produced by the STZ-injured pancreas at physiological blood glucose levels. Method Adult nude mice received 150 mg/kg STZ and 1Â10 6 J1 mouse embryonic stem (ES) cells by i.p. injection. Permanent beta cell depletion of 50% was estimated from the ratio of beta:alpha cells in pancreata from STZ-treated mice compared with control animals after 24 days. Results Transplanted ES cells homed to the STZ-injured pancreas and formed tumours. Immunocytochemical analysis of pancreas-associated ES tumours revealed foci containing insulin/PDX-1 double-positive and glucagonpositive/PDX-1-negative cell clusters associated with PDX-1-positive columnar lumenal epithelium and extensive α-amylase-positive pancreatic acini comprising approximately 0.1% of ES tumour volume. Conclusions/interpretation These data indicate that (1) the adult pancreas produces a milieu of regenerative stimuli following beta cell destruction, and (2) this is not dependent on hyperglycaemic conditions; (3) these regenerative stimuli appear to recapitulate the signalling pathways of embryonic development, since both exocrine and endocrine lineages are produced from PDX-1-positive precursor epithelium. This model will be useful for characterising the regenerative mechanisms in the adult pancreas.

Embryonic Stem Cell Transplantation Correlates With Endogenous Neurogenin 3 Expression and Pancreas Regeneration in Streptozotocin-injured Mice

“…However, the progression to severe hyperglycemia (.400 mg/dl) was significantly (p,0.05) delayed in the ES cell transplant group ( Figure 1D). At sacrifice, pancreata of euglycemic animals appeared normal, with no macroscopic ES tumors, unlike results seen previously following intraperitoneal ES cell transplantation (Takeshita et al 2006).…”

“…However, although we believe it unlikely, we cannot rule out the possibility that the results seen are an effect of STZ. The pattern and time scale (around 3 weeks) of the onset of endogenous b cell neogenesis from progenitors are similar to those of ES cell-derived b cell neogenesis in vivo (Takeshita et al 2006;Kodama et al 2008). In both cases, endocrine pancreas fetal development is comparable: PDX-1 1 ductal epithelium acquires Ngn3 expression and finally leads to endocrine gene expression.…”

“…Previously, we found that b cell damage can induce transplanted embryonic stem (ES) cells to undergo embryonic-like pancreatic endocrine and exocrine neogenesis in vivo from PDX-1 1 ductal epithelium between 15 and 28 days after transplantation (Kodama et al 2008). We also found that transplanted ES cells localized to the injured but not to the normal pancreas (Takeshita et al 2006). In this study, we show that a subset of renal capsule-transplanted ES cells migrating to the pancreas did not differentiate into b cells by themselves, but improved glycemic control in mice following b cell loss.…”

“…Mice were fasted for 7 hr before intraperitoneal injection with 2 mg/kg glucose solution (Sigma). In vivo imaging analysis of transplanted ES cells was conducted in a cryogenically cooled IVIS system (Xenogen; Alameda, CA) as described previously (Takeshita et al 2006). Tumor growth was monitored weekly by whole-body bioluminescent imaging.…”

A histological and immunohistochemical study of beta cells in streptozotocin diabetic rats treated with caffeine

“…Streptozotocin (STZ; N-nitro derivative of glucosamine) has been found to be a cytotoxic chemical to the pancreatic insulin-producing beta-cells of the islets of Langerhans in mammals [6,7]. Injection of STZ results in the degeneration of beta-cells [8].…”