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

Abstract

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.

Cell Therapy for Multiple Sclerosis

“…Additional intracerebellar injection resulted in substantial infiltration and myelination of cerebellar white matter, peduncles, and dorsal brainstem [131]. Importantly, the transplanted shiverers lived significantly longer than their un-transplanted controls, and a fraction of the mice appeared to be completely rescued in terms of survival and neurological disability [131]. In correlation, donor-derived myelin sheaths had the ultra-structural architecture of compact and functional myelin [131].…”

“…Importantly, the transplanted shiverers lived significantly longer than their un-transplanted controls, and a fraction of the mice appeared to be completely rescued in terms of survival and neurological disability [131]. In correlation, donor-derived myelin sheaths had the ultra-structural architecture of compact and functional myelin [131]. Interestingly, fetal and adult-derived human glial precursors demonstrated different functional properties; fetal progenitors emigrated more widely and engrafted more efficiently than adult cells, but the adult progenitors generated oligodendrocytes more efficiently, and myelinated recipient brains much more rapidly and with more axons per donor cell than did fetal cells [42].…”

“…Highly efficient and widespread donor-derived myelination was obtained with these human precursors within a month of transplant to newborn shiverer mice [42], which are congenitally deficient in myelin basic protein [130]. Additional intracerebellar injection resulted in substantial infiltration and myelination of cerebellar white matter, peduncles, and dorsal brainstem [131]. Importantly, the transplanted shiverers lived significantly longer than their un-transplanted controls, and a fraction of the mice appeared to be completely rescued in terms of survival and neurological disability [131].…”

“…In particular, human embryonic stem cell-based therapies might give rise to teratomas, growing from persistent undifferentiated ES cells in the graft [211], or neuroepithelial tumors arising from incompletely differentiated neural cells [212]. Purification of clinical grade and "safe" human ESC-derived glial precursors may be achieved by the same technologies that were developed for isolating these cells from the human brain [42,131].…”

Electrical signalling properties of oligodendrocyte precursor cells

“…Damage to oligodendrocyte precursors, leading to reduced myelination, contributes to mental and physical impairment in periventricular leukomalacia (pre-or perinatal white matter injury leading to cerebral palsy; Volpe, 2001). Adult OPCs may form new myelinating oligodendrocytes in multiple sclerosis, and in brain or spinal cord injury (Levine, 1994;Gensert and Goldman, 1997;Keirstead et al, 1998;McTigue et al, 2001;Levine et al, 2001;Horner et al, 2002), and OPC transplants could serve as a basis for therapeutic remyelination (Windrem et al, 2008;Moreno-Manzano et al, 2009). This article will focus on the electrical signalling properties of OPCs which, as we will describe below, may play a crucial role in their development and their myelination of axons.…”