The Potential Role of Genetically-Modified Pig Mesenchymal Stromal Cells in Xenotransplantation
- 405 Downloads
Mesenchymal stromal cells (MSCs) are known to have regenerative, anti-inflammatory, and immunodulatory effects. There are extensive indications that pig MSCs function satisfactorily across species barriers. Pig MSCs might have considerable therapeutic potential, particularly in xenotransplantation, where they have several potential advantages. (i) pMSCs can be obtained from the specific organ- or cell-source donor pig or from an identical (cloned) pig. (ii) They are easy to obtain in large numbers, negating the need for prolonged ex vivo expansion. (iii) They can be obtained from genetically-engineered pigs, and the genetic modification can be related to the therapeutic goal of the MSCs. We have reviewed our own studies on MSCs from genetically-engineered pigs, and summarize them here. We have successfully harvested and cultured MSCs from wild-type and genetically-engineered pig bone marrow and adipose tissue. We have identified several pig (p)MSC surface markers (positive for CD29, CD44, CD73, CD105, CD166, and negative for CD31, CD45), have demonstrated their proliferation and differentiation (into adipocytes, osteoblasts, and chondroblasts), and evaluated their antigenicity and immune suppressive effects on human peripheral blood mononuclear cells and CD4+T cells. They have identical or very similar characteristics to MSCs from other mammals. Genetically-modified pMSCs are significantly less immunogenic than wild-type pMSCs, and downregulate the human T cell response to pig antigens as efficiently as do human MSCs. We hypothesized that pMSCs can immunomodulate human T cells through induction of apoptosis or anergy, or cause T cell phenotype switching with induction of regulatory T cells, but we could find no evidence for these mechanisms. However, pMSCs upregulated the expression of CD69 on human CD4+ and CD8+ T cells, the relevance of which is currently under investigation. We conclude that MSCs from genetically-engineered pigs should continue to be investigated for their immunomodulatory (and regenerative and anti-inflammatory) effects in pig-to-nonhuman primate organ and cell transplantation models.
KeywordsMesenchymal stromal cells Pig Xenotransplantation
Adipose-derived mesenchymal stromal cells
Aortic endothelial cells
Mixed lymphocyte reaction
Mesenchymal stromal cells
Peripheral blood mononuclear cells
Swine leukocyte antigen
Jiang Li is funded by the China Scholarship Council. Mohamed Ezzelarab is supported in part by the Joseph A. Patrick Research Fellowship in Transplantation of the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh. Studies on xenotransplantation at the Thomas E. Starzl Transplantation Institute are supported in part by CMRF (competitive medical research funding) from the University of Pittsburgh Medical Center, NIH grants #1U19AI090959-01 and #1PO1 HL107152, and by Sponsored Research Agreements between the University of Pittsburgh and Revivicor, Inc., Blacksburg, VA.
Conflict of Interest
DA is an employee of Revivicor Inc., Blacksburg, VA. The other authors report no conflicts of interest.
- 7.Le Blanc, K., Rasmusson, I., Gotherstrom, C., Seidel, C., Sundberg, B., Sundin, M., et al. (2004). Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scandinavian Journal of Immunology, 60, 307–315.PubMedCrossRefGoogle Scholar
- 8.Reinders, M. E., Fijter, J. W., Roelofs, H., Bajema, I. M., Vries, D. K., Schaapherder, A. F., et al. (2013). Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Translational Medicine, 2, 107–111.PubMedCrossRefGoogle Scholar
- 9.Mesenchymal stem cell transplantation in the treatment of chronic allograft nephropathy. (Under investigation, ClinicalTrials.gov Identifier: NCT00659620)Google Scholar
- 10.Perico, N., Casiraghi, F., Introna, M., Gotti, E., Todeschini, M., Cavinato, R. A., et al. (2011). Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clinical Journal of the American Society of Nephrology, 6, 412–422.PubMedCrossRefGoogle Scholar
- 15.Li, J., Andreyeva, O., Chen, M., Marcoa, M., Iwasea, H., Long, C., et al. (2013). Human T cells upregulate CD69 after coculture with xenogeneic genetically-modified pig mesenchymal stromal cells. Cellular Immunology (in press).Google Scholar
- 21.Solari, M. G., Srinivasan, S., Boumaza, I., Unadkat, J., Harb, G., Garcia-Ocana, A., et al. (2009). Marginal mass islet transplantation with autologous mesenchymal stem cells promotes long-term islet allograft survival and sustained normoglycemia. Journal of Autoimmunity, 32, 116–124.PubMedCrossRefGoogle Scholar