In vitro MSC function is related to clinical reaction in vivo

Aileen L Rowland,Carl A Gregory,Amanda Jo Joswig,Ashlee E Watts,Douglas F Antczak,Jiajie Jessica Xu,Kevin J Cummings

doi:10.1186/s13287-018-1037-4

Aileen L Rowland, Carl A Gregory + Show 5 more

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https://doi.org/10.1186/s13287-018-1037-4

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Abstract

BackgroundWe recently demonstrated that intracellular xenogen-contaminated autologous MSCs (FBS) and non-xenogen-contaminated allogeneic (ALLO) MSCs caused an adverse clinical response after repeated intra-articular injection in horses, whereas autologous (AUTO) MSCs did not. Our current objective was to use clinical data from the previous study to compare MSC stemness against adverse response indicated by synovial total nucleated cell count (TNCC) following intra-articular MSC injection.MethodsStemness, quantified by a trilineage differentiation (TLD) score; immunomodulation, quantified by mixed lymphocyte reactions (MLRs); and degree of MHCI expression, quantified by mean fluorescent intensity (MFI); were correlated to the synovial TNCC 24 h after naïve and primed injection.ResultsThere was a trend of a negative correlation (p = 0.21, r = − 0.44) between TLD score and TNCC after primed injection in the ALLO group. Within the ALLO group only, there was a significant positive correlation (p = 0.05, r = 0.77) between MHCI MFI and TNCC after naïve injection and a trend (p = 0.16, r = 0.49) of a positive association of MHCI MFI to TNCC after primed injection. Within the FBS group only, there was a positive correlation (p = 0.04, r = 1) between TNCC and lymphocyte proliferation after both injections.ConclusionsThe trend of a negative correlation of TLD score and TNCC in the ALLO, but not the FBS group, together with the association of MHCI expression and TNCC in the ALLO group, indicates that improved stemness is associated with reduced MSC immunogenicity. When inflammation was incited by xenogen, there was a strong correlation of lymphocyte activation in vitro to adverse response in vivo, confirming that MLRs in vitro reflect MSC immunomodulatory activity in vivo. The relationship of stemness in vitro, suppression of lymphocyte activation in vitro, MHCI expression in vitro, and clinical response in vivo should be further investigated.

Highlights

We recently demonstrated that intracellular xenogen-contaminated autologous mesenchymal stem cells (MSCs) (FBS) and nonxenogen-contaminated allogeneic (ALLO) MSCs caused an adverse clinical response after repeated intra-articular injection in horses, whereas autologous (AUTO) MSCs did not
After the naïve intra-articular injection, there were no significant correlations between trilineage differentiation (TLD) and total nucleated cell count (TNCC) (AUTO, p = 0.18; Fetal bovine serum (FBS), p = 0.25; ALLO, p = 0.43) (Fig. 3a–c)
After the primed intra-articular injection, there were no significant correlations between TLD and TNCC in the AUTO or FBS group (AUTO, p = 0.37; FBS, p = 0.40), but there was a trend (p = 0.21) of a negative correlation (r = − 0.44 in the ALLO group (Fig. 3d–f)

Summary

Introduction

We recently demonstrated that intracellular xenogen-contaminated autologous MSCs (FBS) and nonxenogen-contaminated allogeneic (ALLO) MSCs caused an adverse clinical response after repeated intra-articular injection in horses, whereas autologous (AUTO) MSCs did not. Mesenchymal stem cells (MSCs) have been considered an immune-privileged cell that did not require donor-recipient matching prior to allo-transplantation. This was widely accepted due to the immunologic properties of MSCs in vitro: suppression of stimulated T cells, lack of MHCII expression, relatively low MHCI expression, and production of immunosuppressive cytokines [1]. In a large animal model, we recently demonstrated a local inflammatory response secondary to immune recognition of MSCs after repeated intra-articular. To assess for donor differences due to in vitro stemness, we needed an in vitro measure of MSC quality

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