Human Neural Stem Cells Induce Functional Myelination in Mice with Severe Dysmyelination

Abstract

Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.

Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice

“…These seminal observations suggest that such cells represent a plausible cellular source for cell-based therapy of myelin disorders (1). Although several studies highlighted the impressive therapeutic potential of human fetal NPCs (2)(3)(4)(5), the allogeneic nature of the available NPCs has prevented the bench-tobedside translation of NPC-based therapy for these diseases. In search of an accessible, renewable, and nonimmunogenic source of myelin-forming cells, reprogramming strategies were designed to generate rodent or primate induced pluripotent stem cell-derived NPCs (iPS-NPCs) or oligodendrocyte progenitor cells (iPS-OPCs) (6)(7)(8).…”

CD133/CD140a-Based Isolation of Distinct Human Multipotent Neural Progenitor Cells and Oligodendrocyte Progenitor Cells

“…Although various fetal human preparations can mediate extensive myelination following engraftment into shiverer/rag2 mice [2][3][4], primary fetal cells are limited by the quantity of appropriate tissue samples and/or require extensive expansion in vitro before transplantation. The influence of the shiverer/rag2 environment on oligodendrocyte progenitor cell (OPC) specification and differentiation, and the applicability of these cell preparations for remyelination following acquired demyelination in adult CNS remain open questions.…”

Transcription factor induction of human oligodendrocyte progenitor fate and differentiation

“…Human OPCs have been directly isolated from brain tissue using a variety of surface antigen-based approaches (3)(4)(5)(6). In these studies, the rate of donor-derived myelination was dependent on both developmental stage and purity of the cell population.…”