Immunosuppressant Drugs Mitigate Immune Responses Generated by Human Mesenchymal Stem Cells Transplanted into the Mouse Parenchyma

Abstract

It has been widely accepted that mesenchymal stem cells (MSCs) can evade the immune surveillance of the recipient. However, emerging research cast doubt on whether MSCs are intrinsically immune-privileged. Previously, we observed that the transplantation of human MSCs (hMSCs) into the mouse parenchyma attracted a high infiltration of leukocytes into the injection tract. Thus, in order to reduce the immune responses generated by hMSCs, the aim of this study was to assess which immunosuppressant condition (dexamethasone only, tacrolimus only, or dexamethasone and tacrolimus together) would not only reduce the overall immune response but also enhance the persistence of MSCs engrafted into the caudate putamen of wild-type C57BL/6 mice. According to immunohistochemical analysis, compared to the hMSC only group, the administration of immunosuppressants (for all three conditions) reduced the infiltration of CD45-positive leukocytes and neutrophils at the site of injection. The highest hMSC persistence was detected from the group that received combinatorial administrations of dexamethasone and tacrolimus. Moreover, compared to the immunocompetent WT mouse, higher MSC engraftment was observed from the immunodeficient BALB/c mice. The results of this study support the use of immunosuppressants to tackle MSC-mediated immune responses and to possibly prolong the engraftment of transplanted MSCs.

Combination of Dexamethasone and Tofacitinib Reduces Xenogeneic MSC-Induced Immune Responses in a Mouse Model of Alzheimer’s Disease

“…Moreover, to increase the translatability of the results, clinically relevant doses and administration routes were used in the study [ 17 , 18 ]. Similar to results previously observed from WT mice [ 4 ], we hypothesized that combined therapy involving the use of more than one immunosuppressant will be effective in reducing immune responses generated via hMSCs injected into the parenchyma of the transgenic AD mouse model.…”

“…Previously reported procedures were referred to prepare the cells for injection [ 4 , 24 ]. Human Wharton’s jelly-derived mesenchymal stem cells (Human MSCs; hMSCs) were preconditioned with ethionamide (1261004; Invitrogen, Waltham, MA, USA) and were cultivated in T175 flasks (Thermo Scientific, Waltham, MA, USA) containing MEM alpha 1x (MEMα1x) media (12571-071; Gibco, Waltham, MA, USA) supplemented with 10% foetal bovine serum (FBS, S1480; Biowest, Riverside, MO, USA) and 0.5% Gentamicin (15710-072; Invitrogen, USA) at 37 °C, 5% CO 2 .…”

“…We have reported that in contrast to WT mice that received transplantations of allogeneic MSCs, higher immune responses were exhibited from mice transplanted with xenogeneic MSCs into the parenchyma [ 3 ]. The use of immunosuppressants alleviated the immune response and increased the persistence of human MSCs in the WT mouse brain [ 4 ]. However, whether similar results can be observed in transgenic mouse models have not been investigated.…”

Intracerebroventricular Administration of Human Umbilical Cord Blood—Derived Mesenchymal Stem Cells Induces Transient Inflammation in a Transgenic Mouse Model and Patients with Alzheimer’s Disease

“…Observations were made up to 24 h in this study because fever subsided after 24 h in the clinical trial. Furthermore, according to studies that we have published recently, very few residual human MSCs were identified in the mouse brain one week following MSC transplantation [16,31,32]. Thus, although not extensively studied, since very few residual human MSCs were present in the mouse brain, signs of inflammatory responses may not have been detected at 1 or even 2 weeks following MSC transplantation.…”

Molecular and anatomical roadmap of stroke pathology in immunodeficient mice

“…Despite mounting evidence delineating the importance of inflammation in the stroke pathology, it is poorly described to what extent partial immune deficiency influences the overall stroke outcome. Several immunosuppressed mouse models have been used in preclinical stroke research, most prominent: (a) pharmacological immunosuppression with calcineurin inhibitory drugs (e.g., tacrolimus) that block the development and proliferation of T cells; (b) genetically deficient mice that lack recombination activating gene 2 protein (Rag2 -/- ) required for the generation of mature B and T lymphocytes; and (c) NOD scid gamma (NSG) mice that lack mature T and B lymphocytes, natural killer (NK) cells and have deficiencies in multiple cytokine signalling and innate immunity [11,12]. However, it is unclear to what extent the immunosuppression in these mouse models alter the natural pathology of stroke and may affect the outcome of therapies that require immunosuppression such as human cell-based therapies.…”