Generation of new insulin-secreting beta cells from human adult pancreatic stem cells
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NESCI would be interested in funding / studentship opportunities for the following proposal.
NESCI are interested in industrial partners who may like to collaborate in one of these fields (for a CASE studentship or other awards), or in anyone who is interested in these areas of research (including other academic groups). For further details, please contact Helen Clamp from NESCI.
Project: Generation of new insulin-secreting beta cells from human adult pancreatic stem cells
Lead: Dr James Shaw
Successful transplantation of isolated islets or whole pancreas has allowed a limited number of individuals with diabetes to stop injecting insulin. Widespread clinical implementation is prevented by insufficient suitable donor tissue. Generation of new insulin secreting beta cells from adult pancreatic stem cells may enable insulin independence in many individuals from a single donor.
Human islet-like structures has been attained from putative adult pancreatic stem cells in vitro following culture condition manipulation and growth factor treatment. Insulin biosynthesis and glucose-stimulated secretion remains inadequate for clinical efficacy.
The role of sequential induction and repression of specific transcription factors in the development of β-cells and ultimately mature islets from pancreatic progenitor cells is becoming increasingly apparent. Our group and others have demonstrated induction of insulin gene expression and insulin secretion in rodent ductal and acinar cells following growth factor treatment and transcription factor transfection. Evidence that glucagon-like peptide (GLP-1) may play a pivotal role in inducing end-differentiation in islet precursors is rapidly accumulating. GLP-1 transfection has not previously been evaluated and there is an overall dearth of data relating to human tissue.
The hypothesis to be tested in the current studentship is that:
‘β-cells or mature islets with sufficient glucose-regulated insulin secretion for clinical efficacy can be generated from pancreatic stem cells residing within adult pancreas’. Specific aims are:
To isolate, establish in primary culture and characterise stem cells from human cadaveric donor pancreas
To evaluate the potential for endocrine following growth and differentiation factor treatment (including HGF; betacellulin; GLP-1)
To evaluate the potential for endocrine neogenesis following transcription / differentiation factor gene transfer (including PDX-1; neurogenin-3; ISL-1; GLP-1)
Characterisation before and after transdifferentiation will comprise RT-PCR, Western blot and immunocytochemistry for a range of stem cell and endocrine markers; determination of insulin storage and glucose-stimulated insulin secretion by ELISA; and in vivo validation in diabetic rodents.
1. This work will increase basic understanding of how insulin-producing cells are made which may ultimately lead to new treatments to prevent onset and progression of Type 1 and Type 2 diabetes.
2. Generation of new insulin-producing cells from the expanded stem cells residing within adult pancreas would allow many people with diabetes to benefit from a single donor.
3. Successful expansion from a limited amount of starting material may enable transplants to be performed with a small portion of pancreas from a living donor or the individual with diabetes.
