Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury

Okubo, Toshiteru; Iwanami, Akio; Kohyama, Jun; Itakura, Go; Kawabata, Soya; Nishiyama, Yuichiro; Sugai, Keiko; Ozaki, Masahiro; Iida, Tsuyoshi; Matsubayashi, Kohei; Matsumoto, Morio; Nakamura, Masaya; Okano, Hideyuki

doi:10.1016/j.stemcr.2016.08.015

Cited by 79 publications

(116 citation statements)

References 28 publications

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“…Out of a total of 22 reports that assessed iPSC‐derived neural cells for SCI treatment, the following studies were incorporated into the meta‐analysis . A few studies were excluded, because statistical significance could not be verified, motor recovery was not assessed, used a different scale to assess motor recovery, or focused on a cervical SCI model.…”

Section: Resultsmentioning

confidence: 99%

“…Their results showed deterioration in motor skills after the 47‐day mark and tumor formation from undifferentiated NSCs based on detecting an increase in Nestin + cells . The same line was used by Okubo and collaborators , who reported no tumor formation when the cellular treatment was accompanied with gamma secreting inhibitor (GSI) and resulted in significant motor recovery ( p < .01). Treatment with GSI ensures that NSCs become fully differentiated into appropriate subtypes and prevents tumor formation .…”

Section: Discussionmentioning

confidence: 99%

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Progress in the Use of Induced Pluripotent Stem Cell-Derived Neural Cells for Traumatic Spinal Cord Injuries in Animal Populations: Meta-Analysis and Review

Ramotowski

Villa‐Diaz

2019

Stem Cells Translational Medicine

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Induced pluripotent stem cells (iPSCs) are cells genetically reprogrammed from somatic cells, which can be differentiated into neurological lineages with the aim to replace or assist damaged neurons in the treatment of spinal cord injuries (SCIs) caused by physical trauma. Here, we review studies addressing the functional use of iPSC‐derived neural cells in SCIs and perform a meta‐analysis to determine if significant motor improvement is restored after treatment with iPSC‐derived neural cells compared with treatments using embryonic stem cell (ESC)‐derived counterpart cells and control treatments. Overall, based on locomotion scales in rodents and monkeys, our meta‐analysis indicates a therapeutic benefit for SCI treatment using neural cells derived from either iPSCs or ESCs, being this of importance due to existing ethical and immunological complications using ESCs. Results from these studies are evidence of the successes and limitations of iPSC‐derived neural cells in the recovery of motor capacity. stem cells translational medicine 2019;8:681&693

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Progress in the Use of Induced Pluripotent Stem Cell-Derived Neural Cells for Traumatic Spinal Cord Injuries in Animal Populations: Meta-Analysis and Review

Ramotowski

Villa‐Diaz

2019

Stem Cells Translational Medicine

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“…Okubo et al . () focused on Notch signaling, which plays an important role in maintaining the status of undifferentiated NPCs. Inhibition of this signaling pathway with a γ‐secretase inhibitor (GSI) induced the NPCs to more mature cells with limited proliferation.…”

Section: Methods For Addressing Safety Issue In Human Ipscsmentioning

confidence: 99%

“…; Okubo et al . ). Another is to stop administration of immunosuppressants and activate immunoreactivity leading to the rejection of donor cells (Itakura et al .…”

Section: Challenges For the Clinical Application Of Ipscsmentioning

confidence: 97%

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Applications of induced pluripotent stem cell technologies in spinal cord injury

Nagoshi

Okano

2017

Journal of Neurochemistry

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Numerous basic research studies have suggested the potential efficacy of neural precursor cell (NPC) transplantation in spinal cord injury (SCI). However, in most such studies, the origin of the cells used was mainly fetal tissue or embryonic stem cells, both of which carry potential ethical concerns with respect to clinical use. The development of induced pluripotent stem cells (iPSCs) opened a new path toward regenerative medicine for SCI. iPSCs can be generated from somatic cells by induction of transcription factors, and induced to differentiate into NPCs with characteristics of cells of the central nervous system. The beneficial effect of iPSC-derived NPC transplantation has been reported from our group and others working in rodent and non-human primate models. These promising results facilitate the application of iPSCs for clinical applications in SCI patients. However, iPSCs also have issues, such as genetic/epigenetic abnormalities and tumorigenesis because of the artificial induction method, that must be addressed prior to clinical use. The selection of somatic cells, generation of integration-free iPSCs, and characterization of differentiated NPCs with thorough quality management are all needed to address these potential risks. To enhance the efficacy of the transplanted iPSC-NPCs, especially at chronic phase of SCI, administration of a chondroitinase or semaphorin3A inhibitor represents a potentially important means of promoting axonal regeneration through the lesion site. The combined use of rehabilitation with such cell therapy approaches is also important, as repetitive training enhances neurite outgrowth of transplanted cells and strengthens neural circuits at central pattern generators. Our group has already evaluated clinical grade iPSC-derived NPCs, and we look forward to initiating clinical testing as the next step toward determining whether this approach is safe and effective for clinical use.

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Biomaterial‐Based Defenders Boost Biopharmaceuticals Efficacy for Spinal Cord Injury Treatment: A Review

Zhang

Cao

2023

Adv Materials Inter

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Spinal cord injury (SCI) has seriously affected the lives of patients and brought economic and medical burdens to society. Biopharmaceuticals, including transplanted cells, growth factors, enzyme drugs, and microRNA, present multidimensional therapeutic effects in tissue repair and regeneration, and thus are widely utilized for the treatment of SCI. Nevertheless, they still encounter great challenges. The turbulent microenvironment accompanied by various destructive components following SCI has led to poor stability, low local accumulation, and reduced therapeutic efficacy of biopharmaceuticals. To this end, biomaterial‐based defenders (BBDs) that are capable of resisting the destructive components have shown great promise in improving the survival of transplanted cells or retaining the activity of the protein and nucleic acid drugs for the treatment of SCI. In this review, various types of biopharmaceuticals applied in SCI and their limitations are introduced. The destructive components that threaten the activities of biopharmaceuticals in the rigorous microenvironment are then summarized. In particular, the current research progress about BBDs boosting the efficacy of biopharmaceuticals for the treatment of SCI is illustrated with specific examples. The existing challenges and future perspectives are also provided.

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Pretreatment with a γ-Secretase Inhibitor Prevents Tumor-like Overgrowth in Human iPSC-Derived Transplants for Spinal Cord Injury

Cited by 79 publications

References 28 publications

Progress in the Use of Induced Pluripotent Stem Cell-Derived Neural Cells for Traumatic Spinal Cord Injuries in Animal Populations: Meta-Analysis and Review

Progress in the Use of Induced Pluripotent Stem Cell-Derived Neural Cells for Traumatic Spinal Cord Injuries in Animal Populations: Meta-Analysis and Review

Applications of induced pluripotent stem cell technologies in spinal cord injury

Biomaterial‐Based Defenders Boost Biopharmaceuticals Efficacy for Spinal Cord Injury Treatment: A Review

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