Fibrotic Scar After Spinal Cord Injury: Crosstalk With Other Cells, Cellular Origin, Function, and Mechanism

Li, Ziyu; Yu, Shuisheng; Hu, Xinying; Li, Yiteng; You, Xingyu; Tian, Dan; Cheng, Li; Zheng, Mingquan; Jing, Juehua

doi:10.3389/fncel.2021.720938

Cited by 33 publications

(29 citation statements)

References 92 publications

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“…Fibroblasts’ interactions with other cells within the lesion are not well explored and also require further investigation. We refer to [ 236 ] to review current knowledge on fibroblasts’ cross-talk with other cells after SCI. Furthermore, whether fibroblasts contribute to the neuroinflammation that is present chronically in CNS injuries remains largely unknown [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation

Ayazi

Zivkovic

Hammel

et al. 2022

Cells

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Central nervous system (CNS) trauma activates a persistent repair response that leads to fibrotic scar formation within the lesion. This scarring is similar to other organ fibrosis in many ways; however, the unique features of the CNS differentiate it from other organs. In this review, we discuss fibrotic scar formation in CNS trauma, including the cellular origins of fibroblasts, the mechanism of fibrotic scar formation following an injury, as well as the implication of the fibrotic scar in CNS tissue remodeling and regeneration. While discussing the shared features of CNS fibrotic scar and fibrosis outside the CNS, we highlight their differences and discuss therapeutic targets that may enhance regeneration in the CNS.

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Section: Discussionmentioning

confidence: 99%

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation

Ayazi

Zivkovic

Hammel

et al. 2022

Cells

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“…Surprisingly, the removal of reactive astrocytes did not significantly attenuate the overall expression levels of CSPGs (Anderson et al, 2016 ). Many additional cell types contribute to glial scar formation and may modulate axonal growth and CNS repair after lesions, including fibroblasts, pericytes, oligodendrocyte progenitor cells, and inflammatory cells (Burda and Sofroniew, 2014 ; Li et al, 2021 ; Tran et al, 2022 ). Levels of CSPGs and their mRNA expressions were not significantly reduced at the site of an SCI lesion in astrocyte knockout mice, suggesting that both reactive astrocytes and non-astrocyte cells express inhibitory CSPGs (Anderson et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey

Zhang

Jin

Rodemer

et al. 2022

Front. Mol. Neurosci.

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Axon regrowth after spinal cord injury (SCI) is inhibited by several types of inhibitory extracellular molecules in the central nervous system (CNS), including chondroitin sulfate proteoglycans (CSPGs), which also are components of perineuronal nets (PNNs). The axons of lampreys regenerate following SCI, even though their spinal cords contain CSPGs, and their neurons are enwrapped by PNNs. Previously, we showed that by 2 weeks after spinal cord transection in the lamprey, expression of CSPGs increased in the lesion site, and thereafter, decreased to pre-injury levels by 10 weeks. Enzymatic digestion of CSPGs in the lesion site with chondroitinase ABC (ChABC) enhanced axonal regeneration after SCI and reduced retrograde neuronal death. Lecticans (aggrecan, versican, neurocan, and brevican) are the major CSPG family in the CNS. Previously, we cloned a cDNA fragment that lies in the most conserved link-domain of the lamprey lecticans and found that lectican mRNAs are expressed widely in lamprey glia and neurons. Because of the lack of strict one-to-one orthology with the jawed vertebrate lecticans, the four lamprey lecticans were named simply A, B, C, and D. Using probes that distinguish these four lecticans, we now show that they all are expressed in glia and neurons but at different levels. Expression levels are relatively high in embryonic and early larval stages, gradually decrease, and are upregulated again in adults. Reductions of lecticans B and D are greater than those of A and C. Levels of mRNAs for lecticans B and D increased dramatically after SCI. Lectican D remained upregulated for at least 10 weeks. Multiple cells, including glia, neurons, ependymal cells and microglia/macrophages, expressed lectican mRNAs in the peripheral zone and lesion center after SCI. Thus, as in mammals, lamprey lecticans may be involved in axon guidance and neuroplasticity early in development. Moreover, neurons, glia, ependymal cells, and microglia/macrophages, are responsible for the increase in CSPGs during the formation of the glial scar after SCI.

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“…23,24 The gradual proliferation and migration of fibroblasts also contributes to encapsulation of macrophages in the injured core. 25 Therapeutic approaches to improve SCI recovery must target a diverse set of conditions and cell types over a temporal cascade (Figure 1) and will require combined strategies to bring flexibility needed to treat the complex range of SCIs 26 including providing neural cells to replace damaged or lost cells, targeting the injury microenvironment to remove barriers to regeneration and encourage intrinsic regeneration, and integration with additional connectivity assisting strategies such as electrostimulation and exercise.…”

Section: The Sci Microenvironment and Roles Of Astrocytes Inflammatio...mentioning

confidence: 99%

Human stem cell–derived neurons and neural circuitry therapeutics: Next frontier in spinal cord injury repair

Paredes-Espinosa

Paluh

2022

Exp Biol Med (Maywood)

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Spinal cord injury (SCI) remains a life-altering event that devastates those injured and the families that support them. Numerous laboratories are engaged in preclinical and clinical trials to repair the injured spinal cord with stem cell–derived therapeutics. A new developmental paradigm reveals early bifurcation of brain or trunk neurons in mammals via neuromesodermal progenitors (NMPs) relevant to therapies requiring homotypic spinal cord neural populations. Human-induced pluripotent stem cell (hiPSC) NMP-derived spinal motor neurons generated ex vivo following this natural developmental route demonstrate robust survival in vivo when delivered as suspension grafts or as in vitro preformed encapsulated neuronal circuitry when transplanted into a rat C4-C5 hemicontusion injury site. Use of in vitro matured neurons avoids in vivo differentiation challenges of using pluripotent hiPSC or multipotent neural stem cell (NSC) or mesenchymal stem cell therapeutics. In this review, we provide an injury to therapeutics overview focusing on how stem cell and developmental fields are merging to generate exquisitely matched spinal motor neurons for SCI therapeutic studies. The complexity of the SCI microenvironment generated by trauma to neurons and vasculature, along with infiltrating inflammatory cells and scarring, underlies the challenging cytokine microenvironment that therapeutic cells encounter. An overview of evolving but limited stem cell–based SCI therapies that have progressed from preclinical to clinical trials illustrates the challenges and need for additional stem cell–based therapeutic approaches. The focus here on neurons describes how NMP-based neurotechnologies are advancing parallel strategies such as transplantation of preformed neuronal circuitry as well as human in vitro gastruloid multicellular models of trunk central and peripheral nervous system integration with organs. NMP-derived neurons are expected to be powerful drivers of the next generation of SCI therapeutics and integrate well with combination therapies that may utilize alternate biomimetic scaffolds for bridging injuries or flexible biodegradable electronics for electrostimulation.

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Fibrotic Scar After Spinal Cord Injury: Crosstalk With Other Cells, Cellular Origin, Function, and Mechanism

Cited by 33 publications

References 92 publications

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation

The Composition and Cellular Sources of CSPGs in the Glial Scar After Spinal Cord Injury in the Lamprey

Human stem cell–derived neurons and neural circuitry therapeutics: Next frontier in spinal cord injury repair

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