Long-Term Safety, Immunologic Response, and Imaging Outcomes following Neural Stem Cell Transplantation for Pelizaeus-Merzbacher Disease

Abstract

Summary Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies.

Bone marrow stromal cells‑derived exosomes target DAB2IP to induce microglial cell autophagy, a new strategy for neural stem cell transplantation in brain injury

“…Briefly, bone marrow stromal cells (MSCs) are potentially useful for the treatment of a number of brain injury diseases due to their abundant supply. An increasing number of studies have reported their prospective functions and applications (9,(12)(13)(14)(15)(16)(17). In the present study, 758 miRNAs were detected in exosomes of MSCs using Agilent miRNA chip technology, where rno-miR-32-3p, rno-miR-211-3p, rno-miR-188-5p and rno-miR-465-5p were first found in the exosomes of MSCs.…”

“…The results revealed that treated rats had significantly recovered motor function. However, immune reactions induced by neural stem cell application and the resulting rejection continue to be the main challenges obstructing their current clinical application ( 8 , 9 ). Therefore, it is important to understand the mechanism underlying the suppression of immune-related cell activity during neural stem cell transplantation ( 10 , 11 ).…”

Therapeutic Potential of Canine Glial Restricted Progenitors Transplanted in Mouse Model of Demyelinating Disease 

“…However, the transplantation of myelin-producing progenitor cells in patients with PMD was largely ineffective. The closer analysis of clinical data revealed a possible myelination only at a narrow area of implantation site [14,15]. Indeed, we have recently shown in a mouse model of demyelination (shiverer mice; MBP shi/shi , which were also immunode cient to avoid graft rejection; rag2 −/− ), that a robust therapeutic effect of human glial restricted precursors (hGRPs) correlates well with their distribution throughout the entire mouse brain, while mouse GRPs (mGRPs) characterized by limited migration, failed to provide any therapeutic effect [16].…”

Advanced Materials to Enhance Central Nervous System Tissue Modeling and Cell Therapy

“…Depending on the magnitude of disease progression or injury in the host tissue, the microenvironment may be void of trophic support that encourages cell engraftment and function, or even contain inflammatory or toxic factors secreted from reactive astrocytes [ 98–100 ] or microglia that contribute to graft rejection by the host immune system in the CNS, especially for allogeneic cell grafts. [ 101–104 ] Subsequently, over longer timescales after implantation, cells that do not innervate or migrate outward from the injection site or seek out vasculature may function suboptimally, if at all, due to insufficient oxygen/nutrient exposure and thereby reduce the potency of the overall cell graft. [ 105 ]…”