Targeted Resource Generation Projects (TRGP)

Periodically, the BCBC solicits projects through an open competition process to provide support for the development of new reagents and resources that are needed to achieve the overall goals of the consortium.

The current announcement is for a Targeted Resource Generation Project (TRGP) competition to generate scalable, in-vitro models of pure pancreatic beta cells of human origin. These cells should have phenotypic and functional characteristics highly similar to human beta-cells derived from healthy human islets, and meet the following criteria:

Mono-hormonal expression of insulin
Response to relevant secretagogues in the physiological range in-vitro
Scalability to medium or high throughput assays

Beta cells derived from human Pluripotent Stem Cells (PSCs), or cell lines derived from either human pancreas or PSCs would be suitable. Ideally, beta cells generated from any source should have the capability to become quiescent to facilitate development of highly reproducible screening platforms for small molecules or other biologic materials that can induce beta cell proliferation. Cell lines which maintain a stable karyotype would be highly desirable. Successive subcloning of the newly generated line(s) should be performed in order to confirm that a homogenous cell line has been generated. Assessment of regulated insulin secretion in any newly developed beta cell preparation or beta cell line should be performed using sophisticated physiological assays, such as in a cell perifusion system coupled with challenges with a variety of known beta-cell secretagogues. Function should be assessed at different passage levels to ensure that the phenotype is stable and the cells don’t senesce. While creating a scalable source of human insulin beta cell should be the priority of any proposal that comes in response to this announcement, generating a similar source of human alpha cells could be proposed as a parallel effort.

View the RFA page for additional details

2012-2013 TCTRGPA Collaboration Network

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Project Descriptions

Project team leaders are flagged with a yellow star, .

Creating human beta cell lines using hESCs containing doxycycline inducible polyoma middle T antigen

Project Investigators:

Shuibing Chen

Yi-Chieh Nancy Du

View Lay Abstract

Lay Abstract:

<p>Pancreatic β cells play a central role in the pathogenesis of both type 1 and type 2 diabetes. It is believed that type 1 diabetes results from autoimmune destruction of β cells (<a href="#_ENREF_1" title="Cooke, 2008 #5">1</a>). In the progression of type 2 diabetes, β cells undergo many complex changes and β cell mass declines gradually. Having a robust supply of functional β cells is important for both replacement therapy and disease modeling of diabetes. Many of current diabetes studies use rodent β cell lines or primary human islets. However, there are significant differences between rodent and human β cells. In addition, the primary human islets are heterogeneous and highly vary from batch to batch. Thus, there is a strong need to create human β cell lines for diabetes studies. Recently, Ravassard et al made a breakthrough in the field by making a human pancreatic β cell line with glucose-inducible insulin secretion. However, this β cell line is derived from tumor and keeps prolifereating, which limits its application for proliferation screening or cell replacement therapy. Human embryonic stem cells, which have been shown to be able to give rise to glucose-responding cells <em>in vivo,</em> will provide a novel resource to create human β cell lines. Compare to adult human islets or fatal pancreatic tissue, hESCs are more accessible and easier to manipulate. We have established an efficient strategy to differentiate hESCs into monohormonal glucose-responding cells. In addition, we have created a method to promote mouse β cells proliferation without forming tumor. Here, we propose to combine our previous expertise to create human β cell lines which have controllable proliferation capacity and little risk of forming tumor after transplantation. These human β cell lines will provide novel materials for middle to large scale drug screening.</p>