Progenitor Cell–Based Treatment of the Pediatric Myelin Disorders

Goldman, Steven A.

doi:10.1001/archneurol.2011.46

Cited by 28 publications

(24 citation statements)

References 70 publications

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“…The potential value of these cells as regenerative vectors has been established not only in experimental models of the hereditary leukodystrophies (Goldman, 2011;Windrem et al, 2008), but also in the adult rat brain, with the demonstration that hESC-derived oligodendroglia can remyelinate demyelinated white matter after radiation injury . In addition, the production of human glial chimeric mice, in which all resident OPCs as well as oligodendrocytes are human , suggested the value of animals engrafted with these cells as models for human myelin disease as well Kondo et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

How to make an oligodendrocyte

2015

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Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation.

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Section: Discussionmentioning

confidence: 99%

How to make an oligodendrocyte

2015

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“…Similarly, the efficiency and extent of myelination required to achieve significant benefit in the hypomyelinating disorders remains unclear, and will depend on disease extent and duration as much as donor cell dispersal and myelinogenic competence in the disease environment. These caveats notwithstanding, there is considerable reason for optimism that cell-based therapy of the pediatric myelin disorders, including not only the storage disorders, but also the primary dysmyelinations, such as Pelizaeus -Merzbacher, vanishing white matter disease, and selected forms of cerebral palsy, may soon prove both feasible and effective (Goldman 2011). Indeed, a recent phase I trial of implanted neural stem cells reported the safety of NSC implants into children with PelizaeusMerzbacher disease, and tentatively claimed evidence of new myelin formation at the sites of implantation (Gupta et al 2012).…”

Section: Challenges In the Use Of Glial Progenitor Grafts For The Chimentioning

confidence: 99%

Glia Disease and Repair—Remyelination

Franklin

Goldman

2015

Cold Spring Harb Perspect Biol

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The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, although this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granular neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet, remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this review, we will review the biology of remyelination, including the cells and signals involved; describe when remyelination occurs and when and why it fails and the consequences of its failure; and discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain. IDENTIFYING REMYELINATIONR emyelination is the process in which new myelin sheaths are restored to axons that have lost their myelin sheaths as a result of primary demyelination. Primary demyelination is the term used to describe the loss of myelin from an otherwise intact axon and should be distinguished from myelin loss secondary to axonal loss-a process called Wallerian degeneration or, misleadingly, secondary demyelination. Remyelination is sometimes referred to as myelin repair. However, this term suggests a damaged but otherwise intact myelin internode being "patched up," a process for which there is no evidence and which does not emphasize the truly regenerative nature of remyelination, in which the prelesion cytoarchitecture is substantially restored. Remyelinated tissue very closely resembles normally myelinated tissue but differs in one important aspect-the newly generated myelin sheaths are typically shorter and thinner than the original myelin sheaths. When myelin is initially formed in the peri-and postnatal period, there is a striking correlation between axon diameter and myelin sheath thickness and length, which is less apparent in remyelination. Instead, myelin sheath thickness and

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“…Since OPCs produce astrocytes as well as oligodendrocytes, and are highly migratory, they might prove useful in rectifying the demyelination-associated enzymatic deficiencies of the lysosomal storage disorders, such as Krabbe disease, metachromatic leukodystrophy and Tay-Sachs disease, among others, as well as the astrocytic pathology of vanishing white matter disease(81). In particular, TALEN and CRISPR/Cas gene editing technologies (82) may allow correction of mutations in PSCs, thus allowing autologous and allogeneic therapy to be assessed across the entire range of hereditary leukodystrophies.…”

Section: Neurologic and Retinal Diseasesmentioning

confidence: 99%

Use of differentiated pluripotent stem cells in replacement therapy for treating disease

Fox

Daley

Goldman

et al. 2014

Science

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171

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Patient-derived pluripotent stem cells (PSC) directed to various cell fates holds promise as source material for treating numerous disorders. The availability of precisely differentiated PSC-derived cells will dramatically impact blood component and hematopoietic stem cell therapies, and should facilitate treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Although an unlimited supply of specific cell types are needed, other barriers must be overcome. This review of the state of cell therapies highlights important challenges. Successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and occasionally needing to control immunologic reactivity. Collaboration among scientists, clinicians, and industry is critical for generating new stem cell-based therapies.

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Progenitor Cell–Based Treatment of the Pediatric Myelin Disorders

Cited by 28 publications

References 70 publications

How to make an oligodendrocyte

How to make an oligodendrocyte

Glia Disease and Repair—Remyelination

Use of differentiated pluripotent stem cells in replacement therapy for treating disease

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