Development of clinically reflective cellular model systems to improve current clinical protocols in cell replacement therapy for Type 1 diabetes

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established December 2016

 

Islet transplantation therapy has revolutionised the treatment of Type 1 diabetes, providing proof of principle that cell replacement therapy can effectively cure patients and restore normal regulation of whole body glucose metabolism. However, at present islet transplants are limited by the availability of donor tissue. Lack of donor tissue also impedes research into new and improved technologies to prolong islet graft survival and function post-transplant.

Our scientists have developed a novel microgravity-based cell clustering technology which generates 3-dimensional cellular aggregates which accurately mimic human islets. These clusters secrete insulin accurately in response to changes in blood glucose, have improved ECM (extracellular matrix) deposition; no demonstrable core necrosis after extended periods (months) in culture; long term replicative capacity; and more clinically reflective gene expression patterns and responses to external stimuli.


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Project timeframes

This project began in 1983 and is ongoing.

Project aims

One of the great challenges in islet transplantation is overcoming the damaging effects of tissue hypoxia (very low oxygen) in the crucial first 48 hours post-transplant. Our scientists have now combined microgravity 3D culture systems with hypoxic cell culture chambers, to allow us to study the detrimental effects of hypoxia on islet graft function in vitro for the first time. This work is providing important new insights into the incredibly damaging effects of hypoxia on islet graft function and is identifying, for the first time, vital new molecular targets that can be utilised to improve islet graft survival and function.

Project findings and impact

Our clinically reflective cellular model systems have provided much of the basic science research underpinning the establishment of the UK Islet Transplant Consortium. The Consortium, chaired by Professor James Shaw (Newcastle), prepared a successful bid to the National Commissioning Group for NHS funding and NICE approval of an integrated UK NHS Islet Transplant Programme.

The Programme, launched nationally in 2008, is the world's first government-funded islet transplant service dedicated to patients with type 1 diabetes. This programme saw the establishment of six transplant centres which provide a cost-effective national program for islet transplantation. These centres were commissioned to deliver a cure for recurrent life-threatening hypoglycaemia. To date, over 70 patients have been successfully transplanted with replacement insulin-producing cells, restoring normal blood glucose control in these individuals and completely eradicating the incidence of life-threatening hypoglycaemia.

Research team

Professor Adrian Bone

James Bockhart

Sandeep Kumar

Nouf Alhasawi

Associate member: 

Dr Claire E Marriott

Output

Programmed cell death gene 4 (PDCD4), a key regulator of pancreatic beta cell survival  By: Kumar, S.*; Alhasawi, N.*; Marriott, C. E.; Bone AJ and Macfarlane WM. Diabetic Medicine  Volume: 32   Special Issue: SI   Supplement: 1   Pages: 36-36   Meeting Abstract: P23   Published: MAR 2015

Optimisation of islet cells for transplantation therapy in Type 1 diabetes By: Alhasawi, N.*; Kumar, S.*; Bone, A. J.; Marriott C E and Macfarlane WM. Diabetic Medicine  Volume: 32   Special Issue: SI   Supplement: 1   Pages: 38-38   Meeting Abstract: P30   Published: MAR 2015

Protection of islet cells for transplantation therapy in Type 1 diabetes  By: Alhasawi, N.*; Kumar, S.*; Marriott CE, Bone AJ and Macfarlane, W. M. Diabetic Medicine  Volume: 31   Special Issue: SI   Supplement: 1   Pages: 31-32   Published: MAR 2014

Differential expression of programmed cell death gene 4 (Pdcd4) and hypoxia-inducible factor 1 alpha (HIF-1alpha) in isolated human pancreatic cancer tissue, as well as in pancreatic cells in culture By: Kumar, S.*; Alhasawi, N.*; Marriott, C. E.; Bone AJ and Macfarlane WM. Diabetic Medicine  Volume: 31   Special Issue: SI   Supplement: 1   Pages: 33-34   Published: MAR 2014

Adaptive response of beta cells to hypoxia: regulation of cell survival and growth By: Barry, M. M.*; Bone, A. J.; Marriott, C. M.; and Macfarlane WM. Diabetic Medicine  Volume: 30   Special Issue: SI   Supplement: 1   Pages: 31-31   Published: MAR 2013

Expression and subcellular localisation of nuclear factor kappa B (NF-kappa B), hypoxia-inducible factor 1 alpha (HIF-1 alpha) and program cell death gene 4 (Pdcd4) in pancreatic cells in response to hypoxia By: Kumar, S.*; Marriott, C. E.; Bone, A. J.; and Macfarlane WM. Diabetic Medicine  Volume: 30   Special Issue: SI   Supplement: 1   Pages: 35-35   Published: MAR 2013

Funding outputs

Finance South East - Novel treatment for diabetes by generation of insulin producing cell clusters - £125,000

Business Investment Fund/CAF - Novel treatment for diabetes by generation of insulin producing cell clusters - £50,000

BBSRC CASE Studentship with Porvair Intl - Biomimetic 3D scaffolds for the cultivation and differentiation of stem cells - £65,000

EPSRC CASE studentship with Biocompatibles - A novel cell-based hypoxic model to evaluate the efficacy, toxicity and mode of action of chemoembolisation agents - £65,000

国产探花 Innovation Award - Diabetes cause, complications and cure - £2,000

Technology outputs

Marriott, C.E., Harrison, M and Macfarlane W.M. (2008) Generation of insulin producing cell clusters using a novel cell culture system. UK Patent Number 0800524.1.

BBSRC CASE Studentship with Porvair Intl

Biomimetic 3D scaffolds for the cultivation and differentiation of stem cells.

Technology output: Directed translation of research on polymer scaffolds into product development at Porvair International, UK.

Partners

Diabetes Research Group projects continue to be enhanced and expanded through strategic national (Exeter, Newcastle, Bristol, Glasgow, Plymouth, Sussex) and international (USA, South Africa, Sweden, Ireland, Germany) academic scientific collaboration, as well as strategic links with local academic and healthcare organisations.