Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury

Assinck, Peggy; Sparling, Joseph S.; Dworski, Shaalee; Duncan, Greg J.; Wu, Di; Liu, Jie; Biernaskie, Jeff; Miller, Freda D.; Tetzlaff, Wolfram

doi:10.1016/j.stemcr.2020.05.017

Cited by 25 publications

(25 citation statements)

References 45 publications

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“…Moreover, the survival and recovery of damaged motoneurons might be attributed to the Akt/ mTOR/p70S6K signaling pathway activation mediated by SKP-SC-EVs. In agreement with these findings, the latest observation reported that SKP-SCs can yield better locomotor outcomes, and mitigate pathological thickening of the bladder wall in chronic SCI, the transplanted SKP-SCs reduced the formation of glial scarring, and greatly strengthened the presence of endogenous SCs, myelinating thousands of sprouting/spared host axons in and around the injury site (26).…”

Section: Discussionsupporting

confidence: 76%

Extracellular vesicles from skin precursor-derived Schwann cells promote axonal outgrowth and regeneration of motoneurons via Akt/mTOR/p70S6K pathway

Wu¹,

Wang²,

Ma³

et al. 2020

Ann Transl Med

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Background: Skin precursor-derived Schwann cells (SKP-SCs) have been shown to benefit the recovery of spinal cord injury (SCI) and peripheral nerve injury (PNI) with motor dysfunction. However, the effect of extracellular vesicles (EVs) from SKP-SCs responsible for neuroregeneration remains unknown.Methods: Based on the obtainment and identification of rat SKP-SCs and their derived EVs, the primary rat injury model of motoneurons resulting from axotomy in vitro or nerve crush in vivo, as well as the secondary rat ischemic hypoxic injury model of motoneuron exposure to oxygen-glucose-deprivation (OGD) in vitro, were treated with EVs from skin precursor-derived Schwann cells (SKP-SC-EVs), respectively.Then, the axonal outgrowth and regrowth was observed and compared, and cell viability as well as the protein kinase B/mammalian target of rapamycin/p70 S6 kinase (Akt/mTOR/p70S6K) signaling pathway was detected, moreover, rapamycin (an mTOR inhibitor) was used to further reveal the underlying molecular mechanism.Results: The internalization of SKP-SC-EVs by neuronal cells was identified in vitro and in vivo. Besides the pro-axonal outgrowth effect of SKP-SC-EVs, prospectively, the treatment of OGD-injured motoneurons with SKP-SC-EVs potentiated the restoration of neuronal viability and axonal regrowth. Furthermore, the axotomizing injury could be improved with SKP-SC-EVs treatment in vitro and in vivo. Finally, it was shown that the application of SKP-SC-EVs could activate the Akt/mTOR/p70S6K signaling pathway that can be abolished by rapamycin.Conclusions: In summary, the addition of SKP-SC-EVs could regulate the cell growth and death signaling pathway mediated by Akt/mTOR/p70S6K, owing to the transmission of cargos in EVs to damaged motoneurons, which leads to axonal regrowth and neuronal resurrection. Thus, SKP-SC-EVs treatment could be a novel promising strategy for improving the axonal outgrowth and regeneration of motoneurons.

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Section: Discussionsupporting

confidence: 76%

Extracellular vesicles from skin precursor-derived Schwann cells promote axonal outgrowth and regeneration of motoneurons via Akt/mTOR/p70S6K pathway

Wu¹,

Wang²,

Ma³

et al. 2020

Ann Transl Med

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“…Apart from Sox10 and Egr2 , overexpression of other TFs expressed in repair Schwann cells, as described above (e.g., Sox2, Jun, Pax3, Egr1 , Olig1 ), may prove beneficial in improving reprogramming efficiencies. In the future, Schwann cells generated via direct differentiation or cellular reprogramming could be used in a stand-alone fashion for transplantation or supplemented in nerve conduits to aid nerve remyelination (Biernaskie et al, 2007 ; Mozafari et al, 2015 ; Sparling et al, 2015 ; Assinck et al, 2020 ). Schwann cells derived from rodent SKPs were demonstrated to successfully repair and remyelinate axons in the injured/diseased CNS as well (Biernaskie et al, 2007 ; Mozafari et al, 2015 ; Sparling et al, 2015 ; Assinck et al, 2020 ).…”

Section: Cellular Reprogramming For Peripheral Nerve Repairmentioning

confidence: 99%

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Balakrishnan

Belfiore

Chu

et al. 2021

Front. Mol. Neurosci.

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Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

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“…Subsequent analysis reveals the survival of transplanted SCLCs for 5 months, their integration into host tissue, neural protection, axonal regeneration, and myelination. Further, the functional analysis reveals improved locomotion after 8 weeks of SCLCs transplantation [ 186 ].…”

Section: Origin and Therapeutic Effects Of Schwann Cell-like Cellsmentioning

confidence: 99%

Schwann Cell-Like Cells: Origin and Usability for Repair and Regeneration of the Peripheral and Central Nervous System

Hopf

Schaefer

Kalbermatten

et al. 2020

Cells

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Functional recovery after neurotmesis, a complete transection of the nerve fiber, is often poor and requires a surgical procedure. Especially for longer gaps (>3 mm), end-to-end suturing of the proximal to the distal part is not possible, thus requiring nerve graft implantation. Artificial nerve grafts, i.e., hollow fibers, hydrogels, chitosan, collagen conduits, and decellularized scaffolds hold promise provided that these structures are populated with Schwann cells (SC) that are widely accepted to promote peripheral and spinal cord regeneration. However, these cells must be collected from the healthy peripheral nerves, resulting in significant time delay for treatment and undesired morbidities for the donors. Therefore, there is a clear need to explore the viable source of cells with a regenerative potential similar to SC. For this, we analyzed the literature for the generation of Schwann cell-like cells (SCLC) from stem cells of different origins (i.e., mesenchymal stem cells, pluripotent stem cells, and genetically programmed somatic cells) and compared their biological performance to promote axonal regeneration. Thus, the present review accounts for current developments in the field of SCLC differentiation, their applications in peripheral and central nervous system injury, and provides insights for future strategies.

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Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury

Cited by 25 publications

References 45 publications

Extracellular vesicles from skin precursor-derived Schwann cells promote axonal outgrowth and regeneration of motoneurons via Akt/mTOR/p70S6K pathway

Extracellular vesicles from skin precursor-derived Schwann cells promote axonal outgrowth and regeneration of motoneurons via Akt/mTOR/p70S6K pathway

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Schwann Cell-Like Cells: Origin and Usability for Repair and Regeneration of the Peripheral and Central Nervous System

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