Neonatal Chimerization with Human Glial Progenitor Cells Can Both Remyelinate and Rescue the Otherwise Lethally Hypomyelinated Shiverer Mouse

Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cell stem cell (Impact Factor: 22.27). 06/2008; 2(6):553-65. DOI: 10.1016/j.stem.2008.03.020
Source: PubMed


Congenitally hypomyelinated shiverer mice fail to generate compact myelin and die by 18-21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal shiverer x rag2(-/-) mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.

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    • "Stem-cell therapy has shown promising results in a number of brain injury or disease models34,35,36,37). Among the therapeutic sources, mesenchymal stem cells (MSCs) are well known for their anti-inflammatory property. "
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    ABSTRACT: Severe intraventricular hemorrhaging (IVH) in premature infants and subsequent posthemorrhagic hydrocephalus (PHH) causes significant mortality and life-long neurological complications, including seizures, cerebral palsy, and developmental retardation. However, there are currently no effective therapies for neonatal IVH. The pathogenesis of PHH has been mainly explained by inflammation within the subarachnoid spaces due to the hemolysis of extravasated blood after IVH. Obliterative arachnoiditis, induced by inflammatory responses, impairs cerebrospinal fluid (CSF) resorption and subsequently leads to the development of PHH with ensuing brain damage. Increasing evidence has demonstrated potent immunomodulating abilities of mesenchymal stem cells (MSCs) in various brain injury models. Recent reports of MSC transplantation in an IVH model of newborn rats demonstrated that intraventricular transplantation of MSCs downregulated the inflammatory cytokines in CSF and attenuated progressive PHH. In addition, MSC transplantation mitigated the brain damages that ensue after IVH and PHH, including reactive gliosis, cell death, delayed myelination, and impaired behavioral functions. These findings suggest that MSCs are promising therapeutic agents for neuroprotection in preterm infants with severe IVH.
    Korean Journal of Pediatrics 06/2014; 57(6):251-6. DOI:10.3345/kjp.2014.57.6.251
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    • "To address this issue, Wang et al. optimized a six-step protocol for the scalable generation of human iPSC-derived OPCs expressing Olig2, PDGFRa, NKX2.2 and Sox10, which could be further purified by FACS based on expression of A2B5, CD140a, CD9 and O4 [8]. Transplantation of hiPSC-derived OPCs into neonatal shiverer mice led to substantial engraftment and myelination in the brain, brainstem and cerebellum, prolonging their survival for several months and were comparable to results obtained using primary OPCs [179] [180]. The production of compact and ultrastructurally mature myelin as well as induction of node of Ranvier formation suggests that these cells can carry out complex biological functions within the host brain environment. "
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    ABSTRACT: The advent of human induced pluripotent stem cells (hiPSCs), reprogrammed in vitro from both healthy and disease-state human somatic cells, has triggered an enormous global research effort to realize personalized regenerative medicine for numerous degenerative conditions. hiPSCs have been generated from cells of many tissue types and can be differentiated in vitro to most somatic lineages, not only for the establishment of disease models that can be utilized as novel drug screening platforms and to study the molecular and cellular processes leading to degeneration, but also for the in vivo cell-based repair or modulation of a patient's disease profile. hiPSCs derived from patients with the neurodegenerative diseases amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and multiple sclerosis have been successfully differentiated in vitro into disease-relevant cell types, including motor neurons, dopaminergic neurons and oligodendrocytes. However, the generation of functional iPSC-derived neural cells that are capable of engraftment in humans and the identification of robust disease phenotypes for modeling neurodegeneration still require a number of key challenges to be addressed. Here, we discuss these challenges and summarize recent progress towards the application of iPSC technology for these four common neurodegenerative diseases.
    New Biotechnology 05/2014; 32(1). DOI:10.1016/j.nbt.2014.05.001 · 2.90 Impact Factor
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    • "The only successful mouse neonatal xenotransplantation (Windrem et al., 2004) was in an inbred shiverer model. Follow-up studies were however all performed in shiverer mice crossed with an immunodeficient rag 2 knockout mice (shi +/+; rag2 −/−) (Sim et al., 2011; Wang et al., 2013; Windrem et al., 2008). To our knowledge, no other studies of neonatal transplants in an outbred mouse line with an intact immune system have been reported. "
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    ABSTRACT: Assessing the efficacy of human stem cell transplantation in rodent models is complicated by the significant immune rejection that occurs. Two recent reports have shown conflicting results using neonatal tolerance to xenografts in rats. Here we extend this approach to mice and assess whether neonatal tolerance can prevent the rapid rejection of xenografts. In three strains of neonatal immune-intact mice, using two different brain transplant regimes and three independent stem cell types, we conclusively show that there is rapid rejection of the implanted cells. We also address specific challenges associated with the generation of humanized mouse models of disease.
    Experimental Neurology 01/2014; 254. DOI:10.1016/j.expneurol.2014.01.007 · 4.70 Impact Factor
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