The Potential Role of Genetically-Modified Pig Mesenchymal Stromal Cells in Xenotransplantation

Abstract

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.

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“…The ease of isolation, the absence of costimulatory receptors, and their immunomodulatory and anti-inflammatory properties of MSCs have led to the profound idea of developing genetically engineered MSCs expressing the desired therapeutic factors as a cell based vector system (20,21). MSCs can be readily transduced with all the known viral and non-viral vectors and can effectively overexpress the transgene (22,23).…”

EP4 Antagonist-Elicited Extracellular Vesicles from Mesenchymal Stem Cells Rescue Cognition/Learning Deficiencies by Restoring Brain Cellular Functions

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