Characterization of the immunomodulatory properties of alveolar bone-derived mesenchymal stem cells

Chen Cao,Susan Tarlé,Darnell Kaigler

doi:10.1186/s13287-020-01605-x

Abstract

BackgroundRecently, mesenchymal stem cells (MSCs) have been shown to have immunomodulatory properties which hold promise for their clinical use to treat inflammatory conditions. Relative to bone marrow-derived MSCs (BMSCs), which are typically isolated from the iliac crest, we have recently demonstrated that MSCs can be predictably isolated from the alveolar bone (aBMSCs) by less invasive means. As such, the aim of this study was to characterize the immunomodulatory properties of aBMSCs relative to BMSCs.MethodsaBMSCs isolated from the human alveolar bone and BMSCs isolated from the human bone marrow of the iliac crest were cultured in the same conditions. Cytokine arrays and enzyme-linked immunosorbent assays (ELISA) of a conditioned medium were used to evaluate differences in the secretion of cytokines. In different functional assays, aBMSCs and BMSCs were cocultured with different types of immune cells including THP-1 monocytes, macrophages, and peripheral blood mononuclear cells (PBMCs) to evaluate their effects on important immune cell functions including proliferation, differentiation, and activation.ResultsThe protein arrays identified interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 to be the major cytokines secreted by aBMSCs and BMSCs. ELISA determined that aBMSCs secreted 268.64 ± 46.96 pg/mL of IL-6 and 196.14 ± 97.31 pg/mL of MCP-1 per microgram of DNA, while BMSCs secreted 774.86 ± 414.29 pg/mL of IL-6 and 856.37 ± 433.03 pg/mL of MCP-1 per microgram of DNA. The results of the coculture studies showed that aBMSCs exhibited immunosuppressive effects on monocyte activation and T cell activation and proliferation similar to BMSCs. Both aBMSCs and BMSCs drove macrophages into an anti-inflammatory phenotype with increased phagocytic ability. Taken together, these data suggest that aBMSCs have potent immunomodulatory properties comparable to those of BMSCs.ConclusionsThe findings of this study have important implications for the development of immunomodulatory stem cell therapies aimed to treat inflammatory conditions using aBMSCs, a more feasible tissue source of MSCs.

Highlights

Mesenchymal stem cells (MSCs) have been shown to have immunomodulatory properties which hold promise for their clinical use to treat inflammatory conditions
The CM were subjected to a prostaglandin E2 (PGE2) parameter assay; Fig. 1 IL-6 and Monocyte chemoattractant protein 1 (MCP-1) are the major cytokines secreted by resting Alveolar bone-derived mesenchymal stem cells (MSCs) (aBMSCs) and bone marrow-derived MSCs (BMSCs). aBMSCs or BMSC-conditioned media were collected and analyzed by a protein array detecting human pro- and anti-inflammatory cytokines and growth factors (a), and enzyme-linked immunosorbent assays (ELISA) kits detecting IL-6 (b) and monocyte chemoattractant protein (MCP)-1 (c). b, c The cytokine levels were normalized according to the DNA content of the cells. n = 3 for each cell type from three different donors the PGE2 concentrations were not detectable
To determine whether the interaction between aBMSCs/BMSCs and THP-1 is attributed to the secretion of soluble factors, CM was incubated in the THP-1-stimulated cultures

Summary

Introduction

Mesenchymal stem cells (MSCs) have been shown to have immunomodulatory properties which hold promise for their clinical use to treat inflammatory conditions. Relative to bone marrow-derived MSCs (BMSCs), which are typically isolated from the iliac crest, we have recently demonstrated that MSCs can be predictably isolated from the alveolar bone (aBMSCs) by less invasive means. MSC injections have shown benefits in patients with steroid-refractory acute GvHD after allogeneic hematopoietic stem cell transplantation [18, 19] In another cell therapy, the European Commission recently approved the first MSC pharmaceutical agent (Alofisel) to treat enterocutaneous fistulas developed in patients with Crohn’s disease, a chronic inflammatory bowel disease [17]. MSC therapy has been recommended as a third-line treatment for acute steroidrefractory GvHD in the UK [18] and has been granted conditional approval for treatment of children with GvHD in other countries throughout the world [17]

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