Biology of Beta Cell Consortium

ES cell line derivation status

NOD-scid IL2rgnull (NSG) and NOD-Rag1null IL2rgnull (NRG) mice support heightened levels of engraftment with human cells and tissues. These engrafted mice allow research on human disease processes without putting individuals at risk.

Embryonic stem cell lines derived from NSG and NRG mice will permit the targeting of mouse genes that encode innate immune components that constrain the engraftment and function of human cell populations. These ES cell lines will also support the creation of knockin mice in which human genes that encode critical human species-specific growth factors and other molecules replace the respective mouse genes. By making these targeted mutations and knockins on the NSG and NRG strain backgrounds, the introgression of genes linked to the knockout of interest during backcrossing is avoided and the development of these models is accelerated.

The development of mouse–human chimeras facilitates in vivo studies on human induced pluripotent stem (iPS) cells obtained from individuals with type 1 diabetes (T1D) without putting individuals at risk. These mouse strains will support engraftment with critical components of the disease process: human beta cells, hematopoietic stem cells (HSC), and thymic epithelium following the differentiation of these components from induced pluripotent stem cells (ips) derived from individuals with T1D. The new generations of humanized mice expressing human HLA and cytokine transgenes and carrying additional targeted mutations that further depress host innate immunity are powerful tools in the investigation of diabetes as well as other human diseases.

Summary of ongoing derivation and testing of ES cell lines from NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG), NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ (NRG), and NOD.CBA/Ls Tyr+/LtJ (NOD Agouti) mice

Supported in part by BCBC seeding grant and signature DIAMOND grant