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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Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation
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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- Award ID(s):
- 2054014
- NSF-PAR ID:
- 10416060
- Date Published:
- Journal Name:
- Cells
- Volume:
- 11
- Issue:
- 15
- ISSN:
- 2073-4409
- Page Range / eLocation ID:
- 2371
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Neural tissue damaged after central nervous system (CNS) injury does not naturally regenerate but is instead replaced by non‐neural fibrotic scar tissue that serves no neurological function. Scar‐free repair to create a more permissive environment for regeneration requires altering the natural injury responses of glial cells. In this work, glycopolymer‐based supramolecular hydrogels are synthesized to direct adaptive glia repair after CNS injury. Combining poly(trehalose‐
co ‐guanosine) (pTreGuo) glycopolymers with free guanosine (fGuo) generates shear‐thinning hydrogels through stabilized formation of long‐range G‐quadruplex secondary structures. Hydrogels with smooth or granular microstructures and mechanical properties spanning three orders of magnitude are produced through facile control of pTreGuo hydrogel composition. Injection of pTreGuo hydrogels into healthy mouse brains elicits minimal stromal cell infiltration and peripherally derived inflammation that is comparable to a bioinert methyl cellulose benchmarking material. pTreGuo hydrogels alter astrocyte borders and recruit microglia to infiltrate and resorb the hydrogel bulk over 7 d. Injections of pTreGuo hydrogels into ischemic stroke alter the natural responses of glial cells after injury to reduce the size of lesions and increase axon regrowth into lesion core environments. These results support the use of pTreGuo hydrogels as part of neural regeneration strategies to activate endogenous glia repair mechanisms. -
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Abstract Retinal diseases are frequently characterized by the accumulation of excessive scar tissue found throughout the neural retina. However, the pathophysiology of retinal fibrosis remains poorly understood, and the cell types that contribute to the fibrotic response are incompletely defined. Here, we show that myofibroblast differentiation of mural cells contributes directly to retinal fibrosis. Using lineage tracing technology, we demonstrate that after chemical ocular injury, Myh11+ mural cells detach from the retinal microvasculature and differentiate into myofibroblasts to form an epiretinal membrane. Inhibition of TGFβR attenuates Myh11+ retinal mural cell myofibroblast differentiation, and diminishes the subsequent formation of scar tissue on the surface of the retina. We demonstrate retinal fibrosis within a murine model of oxygen-induced retinopathy resulting from the intravitreal injection of adipose Myh11-derived mesenchymal stem cells, with ensuing myofibroblast differentiation. In this model, inhibiting TGFβR signaling does not significantly alter myofibroblast differentiation and collagen secretion within the retina. This work shows the complexity of retinal fibrosis, where scar formation is regulated both by TGFβR and non-TGFβR dependent processes involving mural cells and derived mesenchymal stem cells. It also offers a cautionary note on the potential deleterious, pro-fibrotic effects of exogenous MSCs once intravitreally injected into clinical patients.
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Abstract The anti‐malaria drug artesunate and other chemical analogs of artemisinin have demonstrated cytostatic and cytotoxic effects in bacterial and cancer cells. Artemisinin‐derived compounds have also been demonstrated to attenuate fibrosis in preclinical animal models, but the mechanisms by which this inhibition occurs are not well‐understood. We investigated the effects of artesunate on the emergence of the myofibroblast, which is causally implicated in pro‐fibrotic pathologies. CRL‐2097 human dermal fibroblasts were analyzed for protein and transcript expression after treatment with artesunate to analyze fibroblast activation. Proliferation and apoptosis were also evaluated following treatment with artesunate in this cell line. Treatment of human dermal fibroblasts with artesunate antagonized fibroblast activation and pro‐fibrotic extracellular matrix (ECM) deposition, both at basal culture conditions and when cultured in the presence of exogenous transforming growth factor‐β1 (TGF‐β1), a major pro‐fibrotic cytokine. Artesunate‐treated fibroblasts also demonstrated decreased proliferation and increased apoptosis. Transcript analysis by quantitative real‐time polymerase chain reaction demonstrated that artesunate downregulated expression of pro‐fibrotic genes including canonical myofibroblast markers, ECM genes, and several TGF‐β receptors and ligands, and upregulated expression of cell cycle inhibitors and matrix‐metalloproteinases. Together, these data demonstrate that artesunate antagonizes fibroblast activation and decreases expression of pro‐fibrotic genes, while also promoting myofibroblast apoptosis, suggesting that these mechanisms may be responsible in part for the anti‐fibrotic effects of artesunate described previously.
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Human and murine skin wounding commonly results in fibrotic scarring, but the murine wounding model wound-induced hair neogenesis (WIHN) can frequently result in a regenerative repair response. Here, we show in single-cell RNA sequencing comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/cells11152371
