Polarization of Adipose‐Derived Mesenchymal Stem/Stromal Cells by Toll‐Like Receptor Priming

Abstract

Mesenchymal stem/stromal cells (MSCs) are a multipotent stromal cell population of interest for their potential use in cell therapy and immunotherapy due to many interesting traits, such as: their ability to home to injury sites, their ability to differentiate into cells of non‐hematopoietic lineages, and their secretion of paracrine factors with roles in tissue repair and immunomodulation. Similarly to how they home to injury sites, MSCs can also home to tumors, and there exert modulatory functions in the tumor microenvironment. Contrasting MSC effects on tumor progression have been reported in the literature, without great insight into what leads MSCs to exert one function or the other. Manipulating MSCs to exert an anti‐tumorigenic response represents a potential tool for the development of cancer therapeutics utilizing this cell population. In the past, it was shown that MSCs derived from human bone marrow (hBM‐MSCs) can be “polarized”, by toll‐like receptor (TLR) priming, into two phenotypes with opposite effects in tumor progression. In this model, TLR4 priming leads to an immune activating MSC1 phenotype with roles in tumor repression, whereas TLR3 priming induces a stronger immune suppressive MSC2 phenotype that promotes tumor progression. Human adipose‐derived MSCs (hASCs) are an alternative to hBM‐MSCs for therapeutic development, with the advantages of a relative ease of isolation and higher abundance in comparison to their bone marrow counterpart. Although the MSC1 and MSC2 polarization have not been reported in hASCs, we hypothesize that hASCs can also undergo MSC1/MSC2 polarization upon short term and low level TLR stimulation in a similar way to hBM‐MSCs. To test our hypothesis, we primed hASCs with TLR3 or TLR4 agonists and evaluated gene expression changes expected to occur, based on the previously described hBM‐MSCs polarization phenotypes. In our preliminary data, we have been able to observe, consistent with the literature, an upregulation of IL8 in TLR4 primed hASCs, and upregulation of CCL5, IP10 and IDO in TLR3 primed hASCs. On the other hand, gene expression remained unchanged for IL6, TGFβ1, and other associated genes. These results suggest that hASCs can polarize, but there are some differences in the gene signature changes induced by polarization of hBM‐MSCs and hASCs. In addition, some differences have been observed across different donor cells and priming conditions, which could contribute to the immunomodulatory inconsistencies reported in the literature. Current and future experiments aim to further characterize the gene expression signature changes on hASCs upon polarization, and to determine if these polarized phenotypes can, similarly to polarized hBM‐MSCs, differentially modulate tumor progression.Support or Funding InformationPurdue Doctoral Fellowship and Basic Medical Sciences Department, College of Veterinary Medicine, Purdue UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.