MHC Mismatch Inhibits Neurogenesis and Neuron Maturation in Stem Cell Allografts.
Stem cells are being considered for the treatment of many neurological diseases or injuries. The recent development of genetic reprogramming strategies and induced pluripotent stem cells now offers an opportunity to generate stem cells that are perfectly matched for transplantation but there are some conditions when the use of stem cells from another individual may be beneficial. For example, if the patient caries a disease-causing mutation that compromises the function of the stem cell transplant, then the use of healthy but unmatched stem cells may be required to treat the disease. Although mismatched grafts can survive in the brain, the results in this publication show that unmatched stem cells survive but are impaired in their ability to generate new nerve cells or “neurons”. Drugs that are typically used to block immune recognition of the graft were not effective at promoting neuron production while an alternative class of drugs that reduce tissue inflammation were surprisingly effective and caused mismatched stem cell grafts to perform as well as perfectly matched grafts. There are three implications from this work. First, the results show that tissue inflammation present in the diseased or injured brain will impair neuron production and/or survival in stem cell therapies. Second, the results show that the negative impact on neurons is more pronounced when the stem cells are poorly matched to the host. Third, a class of anti-inflammatory drugs not normally considered in transplantation may be very effective in their ability to protect neurons and improve outcome. Our ongoing work is testing these drugs for their ability to improve outcome in models of stem cell therapy for Parkinson’s disease, stroke, and spinal injury.
BACKGROUND: The role of histocompatibility and immune recognition in stem cell transplant therapy has been controversial, with many reports arguing that undifferentiated stem cells are protected from immune recognition due to the absence of major histocompatibility complex (MHC) markers. This argument is even more persuasive in transplantation into the central nervous system (CNS) where the graft rejection response is minimal. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluate graft survival and neuron production in perfectly matched vs. strongly mismatched neural stem cells transplanted into the hippocampus in mice. Although allogeneic cells survive, we observe that MHC-mismatch decreases surviving cell numbers and strongly inhibits the differentiation and retention of graft-derived as well as endogenously produced new neurons. Immune suppression with cyclosporine-A did not improve outcome but non-steroidal anti-inflammatory drugs, indomethacin or rosiglitazone, were able to restore allogeneic neuron production, integration and retention to the level of syngeneic grafts. CONCLUSIONS/SIGNIFICANCE: These results suggest an important but unsuspected role for innate, rather than adaptive, immunity in the survival and function of MHC-mismatched cellular grafts in the CNS.