Polarization of Adipose‐Derived Mesenchymal Stem/Stromal Cells via Toll‐Like Receptor Priming and Potential Synergy with Interleukin‐27 Delivery
Authors: Rivera-Cruz Cosette M. , Figueiredo Marxa L. 
Published: April 2020

Mesenchymal stem/stromal cells (MSCs) are a multipotent stromal cell population of interest for clinical applications in different diseases due to their ability to home to injury, differentiate into non‐hematopoietic cell lineages, and secrete paracrine factors with roles in tissue repair and immunomodulation. Although the manner in which MSCs modulate their many functions are incompletely understood, it has been shown that modulating toll‐like receptor (TLR) signaling can alter MSC activity. Promoting desired effector properties of MSCs represents a potential strategy for the use of these cells in different diseases. It has been reported in the past that MSCs derived from human bone marrow (hBM‐MSCs) can be “polarized”, by TLR priming, into two opposite immunomodulatory phenotypes. TLR4 priming leads to an immune activating MCS1 phenotype with roles in tumor repression, whereas TLR3 priming results in a strong immune suppressive MSC2 phenotype associated with support of tumor progression, and reduction of inflammation in a model of painful diabetic peripheral neuropathy. An alternative subpopulation of MSCs for therapeutic development are human adipose‐derived MSCs (hASCs), with the advantages of a relatively 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. Thus far, we have identified some similarities and differences in the gene expression signatures of the two populations upon TLR priming. Upregulation of IL‐8 was observed for TLR4 stimulated hASCs. CCL5, IDO and IP10 were upregulated in TLR3 stimulated hASCs. These results suggest that hASC polarization may occur in a similar way as in BM‐MSCs. However, no changes were observed in the expression of TGFβ or IL‐6, suggesting cell lineage differences in TLR stimulation response. 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 as well as the key signaling pathways and molecules associated with these changes, and to determine if these polarized phenotypes affect the therapeutic potential of hASCs. Additional work aims to introduce episomal vectors expressing therapeutic genes such as interleukin (IL)‐27 in certain populations of polarized hASC for testing whether polarized hASC can act in synergy with IL‐27 in therapeutic applications such as prostate cancer and rheumatoid arthritis in vivo models of disease.Support or Funding InformationWe acknowledge support from the Purdue Research Foundation 19–20 PRF Research Grant 60000025 (MLF), and Purdue Doctoral Fellowship (CRC).