Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells

Abstract

Objective-To determine if mesenchymal stem cells (MSC) derived from human fetal pancreatic tissue (pMSC) would engraft and differentiate in sheep pancreas following transplantation in utero.Methods-A three-step culture system was established for generating human fetal pMSC. Sheep fetuses were transplanted during the fetal transplant receptivity period with human pMSC and evaluated for in situ and functional engraftment in their pancreas, liver and bone marrow.Results-Isolation and expansion of adherent cells from the human fetal pancreas yielded a cell population with morphologic and phenotypic characteristics similar to MSC derived from bone marrow. This putative stem cell population could undergo multilineage differentiation in vitro. Three to 27 months after fetal transplantation, the pancreatic engraftment frequency (chimeric index) was 79% while functional engraftment was noted in 50% of transplanted sheep. Hepatic and marrow engraftment and expression was noted as well.Conclusion-We have established a procedure for isolation of human fetal pMSC that display characteristics similar to bone marrow derived MSC. In vivo results suggest the pMSC engraft, differentiate and secrete human insulin from the sheep pancreas.

Biological characteristics of stem cells from foetal, cord blood and extraembryonic tissues

“…MSCs derived from foetal liver during the first and second trimester have a reduced osteogenic differentiation potential in comparison with first-trimester foetal blood and with second-trimester spleen, lung and bone marrow MSCs, possibly because of a reduction in osteogenic progenitor numbers (in't Anker et al 2003a,b). Foetal pancreatic MSCs, shown to be capable of differentiating into chondrogenic, osteogenic or adipogenic lineages (Hu et al 2003), can also engraft, differentiate and secrete human insulin in a sheep model (Ersek et al 2010). Moreover, foetal pancreatic ductal stem cells can differentiate into insulin-producing cells in vitro (Yao et al 2004).…”

“…Foetal pancreatic MSCs, shown to be capable of differentiating into chondrogenic, osteogenic or adipogenic lineages (Hu et al 2003), can also engraft, differentiate and secrete human insulin in a sheep model (Ersek et al 2010). Moreover, foetal pancreatic ductal stem cells can differentiate into insulin-producing cells in vitro (Yao et al 2004).…”

Fetal Liver-Derived Mesenchymal Stem Cell Engraftment After Allogeneic In Utero Transplantation into Rabbits

“…Thus, human MSCs from several sources have been shown to reconstitute different tissues after human-sheep [9][10][11], human-mouse [12,13], or human-rat [14] xenogeneic in utero transplantation. Furthermore, proof-of-principle studies have recently stressed the therapeutic potential of human fetal MSCs for the treatment of severe osteogenesis imperfecta both after xenogeneic transplantation into the corresponding mouse model [15], and after allogeneic transplantation in an immunocompetent, HLA-incompatible patient [16].…”

Engraftment Potential of Adipose Tissue-Derived Human Mesenchymal Stem Cells After Transplantation in the Fetal Rabbit

“…Therefore, special efforts are being focused in the development of preclinical in utero MSC transplantation studies. In fact, several reports have confirmed that fetal administration of MSCs resulted in correct engraftment and differentiation of transplanted cells [11][12][13].…”