Achieving Stable Human Stem Cell Engraftment and Survival in the CNS: Is the Future of Regenerative Medicine Immunodeficient?

Anderson, Aileen J.; Haus, Daniel L.; Hooshmand, Mitra J.; Perez, H D; Sontag, Christopher J.; Cummings, Brian J.

doi:10.2217/rme.11.22

Cited by 81 publications

(92 citation statements)

References 250 publications

(124 reference statements)

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“…Considering their clinical application, the precise mechanisms of action of many stem-cell populations still remain to be elucidated at the preclinical level. Theoretically, possible mechanisms of therapeutic effects of stem-cell transplantation in CNS diseases/injuries include: (a) cell replacement for lost cells after CNS damage (e.g., forming new oligodendrocytes and/or neurons) and (b) trophic support to increase survival of host neural cells and host-mediated regeneration, repair, and/or plasticity [3,41]. While the latter mechanisms include short-term neurotrophic/neuroprotective effects, the graft-derived cells should differentiate into the appropriate cells and survive over the long-term to achieve functional recovery through the cell replacement.…”

Section: Discussionmentioning

confidence: 99%

“…3). Thus, rather than using conventional pharmacologic immunosuppression, to minimize immunological barriers for long-term engraftment after SCI, we adopted NOD/SCID mice as hosts, which could be used as recipients even in the xenograft of human cells into SCI mice models [3,41]. While NOD/SCID mice have neutrophils, macrophages, and microglia resulting in innate immune responses, we observed similar survival rate of shi-NS/PCs and wt-NS/PCs for all through 6 weeks and identical differentiation characteristics in the injured spinal cord.…”

Section: Discussionmentioning

confidence: 99%

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Significance of Remyelination by Neural Stem/Progenitor Cells Transplanted into the Injured Spinal Cord

et al. 2011

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Previous reports of functional recovery from spinal cord injury (SCI) in rodents and monkeys after the delayed transplantation of neural stem/progenitor cells (NS/PCs) have raised hopes that stem cell therapy could be used to treat SCI in humans. More research is needed, however, to understand the mechanism of functional recovery. Oligodendrocytes derived from grafted NS/PCs remyelinate spared axons in the injured spinal cord. Here, we studied the extent of this remyelination's contribution to functional recovery following contusive SCI in mice. To isolate the effect of remyelination from other possible regenerative benefits of the grafted cells, NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PCs) were used in this work alongside wild-type NS/PCs (wt-NS/PCs). shi-NS/PCs behaved like wt-NS/PCs in vitro and in vivo, with the exception of their myelinating potential. shi-NS/ PC-derived oligodendrocytes did not express myelin basic protein in vitro and formed much thinner myelin sheaths in vivo compared with wt-NS/PC-derived oligodendrocytes. The transplantation of shi-NS/PCs promoted some locomotor and electrophysiological functional recovery but significantly less than that afforded by wt-NS/PCs. These findings establish the biological importance of remyelination by graft-derived cells for functional recovery after the transplantation of NS/PCs into the injured spinal cord.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Significance of Remyelination by Neural Stem/Progenitor Cells Transplanted into the Injured Spinal Cord

et al. 2011

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“…In vivo studies were conducted in NOD-scid mice to enable survival of donor human cells, as described previously (33,34,67,68) and under Materials and Methods. Importantly, although NOD-scid mice exhibit deficits in adaptive immunity, they demonstrate innate immune responses and histopathological characteristics comparable to other mouse strains following SCI (22,23).…”

Section: Blockade Of C1q and C3a In Pmn-cm Reduces Astroglial Differementioning

confidence: 93%

“…9, 10) data, in which donor human cells were xenografted into the mouse spinal cord. NOD-scid mice are T cell and B cell deficient, making this model optimal and widely used for xenotransplantation studies in which the survival of donor human cells is a critical variable (22). Importantly, although NOD-scid mice exhibit deficits in adaptive immunity, they demonstrate innate immune responses and histopathological characteristics comparable to other mouse strains following SCI (23).…”

Section: Generation Of Pmn or Mf-cmmentioning

confidence: 99%

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

Hooshmand

Nguyen

Piltti

et al. 2017

The Journal of Immunology

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Inflammatory processes play a key role in pathophysiology of many neurologic diseases/trauma, but the effect of immune cells and factors on neurotransplantation strategies remains unclear. We hypothesized that cellular and humoral components of innate immunity alter fate and migration of human neural stem cells (hNSC). In these experiments, conditioned media collected from polymorphonuclear leukocytes (PMN) selectively increased hNSC astrogliogenesis and promoted cell migration in vitro. PMN were shown to generate C1q and C3a; exposure of hNSC to PMN-synthesized concentrations of these complement proteins promoted astrogliogenesis and cell migration. Furthermore, in vitro, Abs directed against C1q and C3a reversed the fate and migration effects observed. In a proof-of-concept in vivo experiment, blockade of C1q and C3a transiently altered hNSC migration and reversed astroglial fate after spinal cord injury. Collectively, these data suggest that modulation of the innate/humoral inflammatory microenvironment may impact the potential of cell-based therapies for recovery and repair following CNS pathology.

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“…The migration of engrafted cells toward damaged tissue is a critical step in stem cell therapy, and further work is required to elucidate the chemokine signaling networks that regulate this process (16,31,95). The risk of immunorejection also weighs heavily on any transplantation study (9). These issues impact the assessment of stem cell safety and efficacy in efforts to translate animal studies to the clinic (9).…”

Section: Stem Cell Therapy To Ameliorate Radiation-induced Cognitive mentioning

confidence: 99%

Stem Cell Therapies for the Treatment of Radiation-Induced Normal Tissue Side Effects

Benderitter

Caviggioli

Chapel

et al. 2014

Antioxidants & Redox Signaling

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Significance: Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed. Recent Advances: Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration. Critical Issues: While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiationinduced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice. Future Directions: Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment. Antioxid. Redox Signal. 21, 338-355.

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Achieving Stable Human Stem Cell Engraftment and Survival in the CNS: Is the Future of Regenerative Medicine Immunodeficient?

Cited by 81 publications

References 250 publications

Significance of Remyelination by Neural Stem/Progenitor Cells Transplanted into the Injured Spinal Cord

Significance of Remyelination by Neural Stem/Progenitor Cells Transplanted into the Injured Spinal Cord

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

Stem Cell Therapies for the Treatment of Radiation-Induced Normal Tissue Side Effects

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