Immunostimulatory Effects of Mesenchymal Stem Cell‐Derived Neurons: Implications for Stem Cell Therapy in Allogeneic Transplantations

Abstract

Mesenchymal stem cells (MSCs) differentiate along various lineages to specialized mesodermal cells and also transdifferentiate into cells such as ectodermal neurons. MSCs are among the leading adult stem cells for application in regenerative medicine. Advantages include their immune‐suppressive properties and reduced ethical concerns. MSCs also show immune‐enhancing functions. Major histocompatibility complex II (MHC‐II) is expected to be downregulated in MSCs during neurogenesis. Ideally, “off the shelf” MSCs would be suited for rapid delivery into patients. The question is whether these MSC‐derived neurons can reexpress MHC‐II in a milieu of inflammation. Western analyses demonstrated gradual decrease in MHC‐II during neurogenesis, which correlated with the expression of nuclear CIITA, the master regulator of MHC‐II expression. MHC‐II expression was reversed by exogenous IFNY. One‐way mixed lymphocyte reaction with partly differentiated neurons showed a stimulatory effect, which was partly explained by the release of the proinflammatory neurotransmitter substance P (SP), cytokines, and decreases in miR‐130a and miR‐206. The anti‐inflammatory neurotransmitters VIP and CGRP were decreased at the peak time of immune stimulation. In summary, MSC‐derived neurons show decreased MHC‐II expression, which could be reexpressed by IFNY. The release of neurotransmitters could be involved in initiating inflammation, underscoring the relevance of immune responses as consideration for stem cell therapies.

Stem Cells and Regenerative Medicine: Accomplishments to Date and Future Promise

“…The repertoire of cytokines secreted by MSCs includes macrophage colony stimulating factor (M-CSF), IL-6, IL-8, IL-12, hepatocyte growth factor, tumor necrosis factor-alpha (TNF-α) and the immunosuppressive cytokines IL-10 and TGF-β56, 57. Furthermore, MHC-II is decreased when the MSCs differentiate into specialized cells, such as neurons58. Due to these characteristics, MSCs have been extensively explored for applications in regenerative medicine.…”

“…While MSCs are a desirable stem cell source for ‘off-the-shelf’ therapy because of their weak immunogenicity, in vitro studies demonstrate re-expression of MHC-II on the MSC-derived neurons in the presence of low levels of IFNγ58. This finding is highly significant, as future therapies with MSCs need to address the possibility that there could be eventual rejection of the implanted cells by the host immune system.…”

Adult mesenchymal stem cells in neural regeneration and repair: Current advances and future prospects (Review)

“…This is significant since the therapeutic use of MSCs may involve transplantation within an inflammatory microenvironment. This has a fundamental implication for the use of MSCs in regenerative medicine, specifically neural repair (90). For example, if MSC-derived neurons are implanted in an allogeneic host with spinal cord injury and the host encounters an infection, they may have the potential to revert back to their APC function by re-expressing MHC-II (90).…”

Mesenchymal Stem Cells: Engineering Regeneration

“…However, rejection of marrow stromal cells in MHC class I and class II‐mismatched recipients has been reported, underscoring the relevance of the immune response in the outcome of stem cell therapy 3 . While recognizing the desirable combination of multipotent potential and tolerogenicity, Castillo and colleagues in the current issue of Clinical and Translational Science raise a cautionary note with regard to the use of the allogeneic approach, as mesenchymal stem cell interaction with the microenvironment could trigger (re)expression of MHC‐II antigens compromising the fate of implanted cells 7 . Additional studies are therefore needed to optimally translate mesenchymal stem cell therapy in the clinical setting.…”

“…Culture‐based expansion offers not only the opportunity to produce en masse a large pool of naïve stem cells, but also to derive progeny honed for lineage specification away from multipotency and into tissue‐restricted cytopoiesis (Figure 2). 7,9 In this regard, high‐throughput technological platforms have been applied to decode the genomic, proteomic, and metabolomic foundation under‐lying guided differentiation 10–13 . Derivation and characterization of specialized mesenchymal stem cell subpopulations, and their selective application to specific disease conditions is an emerging strategy for enhanced therapeutic outcome 14 .…”