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Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment.

ABSTRACT: Spinal cord injury results in irreversible tissue damage followed by a very limited recovery of function. In this study we investigated whether transplantation of undifferentiated human induced pluripotent stem cells (hiPSCs) into the injured rat spinal cord is able to induce morphological and functional improvement. hiPSCs were grafted intraspinally or intravenously one week after a thoracic (T11) spinal cord contusion injury performed in Fischer 344 rats. Grafted animals showed significantly better functional recovery than the control rats which received only contusion injury. Morphologically, the contusion cavity was significantly smaller, and the amount of spared tissue was significantly greater in grafted animals than in controls. Retrograde tracing studies showed a statistically significant increase in the number of FB-labeled neurons in different segments of the spinal cord, the brainstem and the sensorimotor cortex. The extent of functional improvement was inversely related to the amount of chondroitin-sulphate around the cavity and the astrocytic and microglial reactions in the injured segment. The grafts produced GDNF, IL-10 and MIP1-alpha for at least one week. These data suggest that grafted undifferentiated hiPSCs are able to induce morphological and functional recovery after spinal cord contusion injury.

SUBMITTER: Bellak T

PROVIDER: S-EPMC7772333 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment.

Bellák Tamás T Fekécs Zoltán Z Török Dénes D Táncos Zsuzsanna Z Nemes Csilla C Tézsla Zsófia Z Gál László L Polgári Suchitra S Kobolák Julianna J Dinnyés András A Nógrádi Antal A Pajer Krisztián K

Scientific reports 20201229 1

Spinal cord injury results in irreversible tissue damage followed by a very limited recovery of function. In this study we investigated whether transplantation of undifferentiated human induced pluripotent stem cells (hiPSCs) into the injured rat spinal cord is able to induce morphological and functional improvement. hiPSCs were grafted intraspinally or intravenously one week after a thoracic (T11) spinal cord contusion injury performed in Fischer 344 rats. Grafted animals showed significantly b ...[more]

PMID: 33376249

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Project description:Grafted astroglia/astrocytes exhibit neuroprotective effects and improve functional recovery after injury to the central nervous system. This study sought to elucidate their ability to repair spinal cord lesions and the underlying mechanisms. Methods: Complete spinal transection, transplantation of astroglia generated from human ESC-derived neural progenitor cells (NPC-Astros) or Olig2-GFP knock-in progenitors (Olig2PC-Astros), and immunostaining were used to determine the survival of astroglia. CUBIC tissue-clearing, immunostaining, electromyography, and functional tests such as the Basso Mouse Scale score and gait analysis were applied to analyze the recovery of the lesion area, axon regeneration, synapse formation, and motor function. Sholl analysis, immunostaining, depletion of anti-inflammatory microglia, and western blotting were employed to explore the cellular and molecular mechanisms underlying spinal cord repair. Results: Grafted NPC- or Olig2PC-Astros survived in the lesion area and assisted wound healing by reducing scar formation and promoting regrowth of descending serotonergic axons and synapse reformation beyond the lesion area. These positive effects resulted in increased Basso Mouse Scale scores and improved hindlimb function as determined by electromyography and gait analysis. Activated microglia in the lesion area were shifted towards an anti-inflammatory phenotype after transplantation of NPC- or Olig2PC-Astros, and depletion of anti-inflammatory microglia reversed the observed improvements in the lesion area and axon regeneration. Transplantation of NPC- or Olig2PC-Astros elevated the expression of interleukin-4 and promoted the phenotypic shift of microglial via interleukin-4 downstream signaling. Conclusion: Our findings indicate that grafted human ESC-derived NPC- or Olig2PC-Astros promote recovery of the injured spinal cord by shifting microglia towards an anti-inflammatory state in the lesion area and activating interleukin-4 signaling.

Project description:BackgroundSpinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.Methods and principal findingsWith the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery.Conclusions and significanceTransplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.

Dataset Information

Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment.

Publications

Grafted human induced pluripotent stem cells improve the outcome of spinal cord injury: modulation of the lesion microenvironment.

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