Single-cell RNA sequencing reveals Nestin+ active neural stem cells outside the central canal after spinal cord injury

Shu, Muya; Xue, Xu; Nie, Hu; Wu, Xianming; Sun, Minghan; Qiao, Lianyong; Li, Xing; Bai, Xu; Xiao, Zhifeng; Zhao, Yannan; Fan, Yongheng; Chen, Bing; Zhang, Jixiang; Shi, Yang; Yang, Yaming; Lu, Falong; Dai, Jianwu

doi:10.1007/s11427-020-1930-0

Cited by 30 publications

(29 citation statements)

References 54 publications

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“…In vitro, dNSCs are responsive to fibroblast growth factor (FGF) and epidermal growth factor (EGF), and form clonally-derived, multipotent, and self-renewing neurospheres in these conditions [ 71 ]. Following injury, dNSCs are activated [ 72 ] to proliferate and generate progeny and migrate to the site of injury where they primarily give rise to glial cells [ 48 , 73 ]. Lineage tracking studies have revealed that ~95% of the progeny differentiate into astrocytes which contribute to the glial scar and ~2–5% differentiate into oligodendrocytes [ 29 , 32 , 74 ].…”

Section: Adult Neural Stem Cells: a Heterogeneous Population Of Cellsmentioning

confidence: 99%

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

Gilbert

Lakshman

Lau

et al. 2022

Cells

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Spinal cord injury (SCI) affects millions of individuals worldwide. Currently, there is no cure, and treatment options to promote neural recovery are limited. An innovative approach to improve outcomes following SCI involves the recruitment of endogenous populations of neural stem cells (NSCs). NSCs can be isolated from the neuroaxis of the central nervous system (CNS), with brain and spinal cord populations sharing common characteristics (as well as regionally distinct phenotypes). Within the spinal cord, a number of NSC sub-populations have been identified which display unique protein expression profiles and proliferation kinetics. Collectively, the potential for NSCs to impact regenerative medicine strategies hinges on their cardinal properties, including self-renewal and multipotency (the ability to generate de novo neurons, astrocytes, and oligodendrocytes). Accordingly, endogenous NSCs could be harnessed to replace lost cells and promote structural repair following SCI. While studies exploring the efficacy of this approach continue to suggest its potential, many questions remain including those related to heterogeneity within the NSC pool, the interaction of NSCs with their environment, and the identification of factors that can enhance their response. We discuss the current state of knowledge regarding populations of endogenous spinal cord NSCs, their niche, and the factors that regulate their behavior. In an attempt to move towards the goal of enhancing neural repair, we highlight approaches that promote NSC activation following injury including the modulation of the microenvironment and parenchymal cells, pharmaceuticals, and applied electrical stimulation.

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Section: Adult Neural Stem Cells: a Heterogeneous Population Of Cellsmentioning

confidence: 99%

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

Gilbert

Lakshman

Lau

et al. 2022

Cells

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“…In addition, research has reported that UCHL1 could spatially mediates neurogenesis in the embryonic brain by regulating the morphology of neural progenitor cells (NPCs) 27 . Moreover, UCHL1 has been shown to be signi cantly upregulated in the Nestin + active NSCs post-SCI 9 . However, the potential effects of UCHL1 on spinal cord Nestin + NSCs remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Nestin + cells from the spinal cord could neurospheres and differentiate into neurons, astrocytes and oligodendrocytes in vitro 3,4 . They are quiescent in the normal spial cord and remarkably increased after spinal cord injury (SCI) 9 . Single-cell RNA sequencing analysis has revealed that genes of active NSCs were signi cantly upregulated in Nestin + cells outside the central canal upon SCI 9 , suggesting they are likely act as the endogenous NSCs in the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

“…They are quiescent in the normal spial cord and remarkably increased after spinal cord injury (SCI) 9 . Single-cell RNA sequencing analysis has revealed that genes of active NSCs were signi cantly upregulated in Nestin + cells outside the central canal upon SCI 9 , suggesting they are likely act as the endogenous NSCs in the spinal cord. Although quickly activated in response to SCI, unfortunately, the activation and neurogenesis from endogenous NSCs are extremely limited in the adult spinal cord in vivo 10,11,12 .…”

Section: Introductionmentioning

confidence: 99%

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UCHL1 inhibited by reactive astrocytes facilitates aggregates clearance to promote neural stem cell activation

Ding

Chu

Xia

et al. 2022

Preprint

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Activation of the endogenous neural stem cells (NSCs) is critically important for the adult neurogenesis. However, NSC activation is extremely limited in the non-neurogenic spinal cord after spinal cord injury (SCI). Recent evidence suggests that accumulation of protein aggregates impedes quiescent NSC activation. Here, we found that ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, functioned to facilitate NSC activation by clearing protein aggregations through ubiquitin-proteasome pathway. Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and the subsequent protein aggregations clearance to restrict NSC activation via C3/C3aR signaling. Upregulation of UCHL1 and blockade of reactive astrocytes or C3/C3aR pathway efficiently enhanced Nestin+ NSC activation after SCI. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, providing a promising strategy and novel molecular targets for SCI repair.

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“…Instead, they were specifically enriched not only in the spinal neurons (NeuN + ) (Figure 1G), but also co-localized with Nestin + cells, a specific marker for spinal cord endogenous NSCs [35][36][37] . The level of UCHL1 was remarkably decreased in NSCs after SCI (Figures 1H and 1I), suggesting that it might be involved in SCI-induced biological process of spinal cord NSCs.…”

Section: Introductionmentioning

confidence: 99%

UCHL1 inhibited by A1 astrocytes facilitates aggregates clearance to promote neural stem cells activation after spinal cord injury

Ding¹,

Chu

Xia

et al. 2021

Preprint

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Spinal cord injury (SCI) is a devastating central nervous system (CNS) disease with no satisfying therapies available. Mobilizing endogenous neural stem cells (NSCs) to trigger intrinsic regeneration exhibits promising potentials for SCI repair. However, neurogenesis from endogenous NSCs is extremely restricted in the non-neurogenic spinal cord after SCI. Accumulation of protein aggregates has been shown to impede quiescent NSCs activation and the subsequent neurogenesis. Here, we found that ubiquitin c-terminal hydrolase l-1 (UCHL1), a deubiquitinating enzyme, functioned to regulate NSCs activation and neurogenesis by reducing protein aggregations through ubiquitin-proteasome pathway (UPP) in vitro. Upregulation of UCHL1 in spinal cord NSCs of rats with complete transection SCI efficiently enhanced NSCs proliferation and neurogenesis, leading to significantly improved functional outcomes. Based on protein microarray analysis of cerebrospinal fluid (CSF), our results revealed that A1 reactive astrocytes acted to restrict NSCs neurogenesis by negatively regulating UCHL1-depentdent protein aggregates removal via the C3/Nrf2 signaling. Indeed, blockade of A1 astrocytes using neutralizing antibodies after SCI also led to NSCs activation, increased neurogenesis and remarkably enhanced motor function recovery. This study not only revealed a novel mechanism regulating NSCs-medicated neurogenesis in the spinal cord, but also provided new molecular targets for neural repair strategies after SCI.

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Single-cell RNA sequencing reveals Nestin+ active neural stem cells outside the central canal after spinal cord injury

Cited by 30 publications

References 54 publications

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

UCHL1 inhibited by reactive astrocytes facilitates aggregates clearance to promote neural stem cell activation

UCHL1 inhibited by A1 astrocytes facilitates aggregates clearance to promote neural stem cells activation after spinal cord injury

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