Astrocyte-Secreted Matricellular Proteins in CNS Remodelling during Development and Disease

Abstract

Matricellular proteins are secreted, nonstructural proteins that regulate the extracellular matrix (ECM) and interactions between cells through modulation of growth factor signaling, cell adhesion, migration, and proliferation. Despite being well described in the context of nonneuronal tissues, recent studies have revealed that these molecules may also play instrumental roles in central nervous system (CNS) development and diseases. In this minireview, we discuss the matricellular protein families SPARC (secreted protein acidic and rich in cysteine), Hevin/SC1 (SPARC-like 1), TN-C (Tenascin C), TSP (Thrombospondin), and CCN (CYR61/CTGF/NOV), which are secreted by astrocytes during development. These proteins exhibit a reduced expression in adult CNS but are upregulated in reactive astrocytes following injury or disease, where they are well placed to modulate the repair processes such as tissue remodeling, axon regeneration, glial scar formation, angiogenesis, and rewiring of neural circuitry. Conversely, their reexpression in reactive astrocytes may also lead to detrimental effects and promote the progression of neurodegenerative diseases.

Exosomes in stroke pathogenesis and therapy

“…Connective tissue growth factor (CTGF) and RhoA are putative targets of miR-133b and are known to suppress neurite growth (118). In vitro, incubation of cortical neurons with miR-133b-elevated exosomes downregulated RhoA and enhanced neurite outgrowth, whereas treatment of astrocytes with miR-133b-elevated exosomes suppressed CTGF, which is mainly expressed by astrocytes (119,124). Collectively, these data indicate that MSCderived exosomes may be used as vehicles to transport miRNAs that modulate genes in the recipient neurons and astrocytes.…”

Promoting brain remodeling to aid in stroke recovery

“…In vitro studies showed that ischemic brain tissue elevated miR-133b levels in MSC-released exosomes. In the brain, CTGF is mainly expressed by astrocytes [71]. The treatment of astrocytes with the exosomes containing high levels of miR-133b downregulated CTGF expression, while incubation of neurons with the exosomes reduced RhoA expression and promoted neurite outgrowth [72].…”

Dissecting brain tumor growth and metastasis in vitro and ex vivo

“…The distribution and composition of these ECM components in the developing rodent brain is changing during embryonal and postnatal phases and reaches a mature stage at postnatal day 20. [25] However, disease-associated remodeling of the CNS ECM has been observed after injury, [25][26][27][28] suggesting that growing primary neoplasms in the brain may also alter the surrounding ECM. Relatively little change in the expression levels of a small set of proteins in normal brain tissue and in brain tissue surrounding invasive glioblastoma was observed in a recent study, [29] except for Tenascin-R and CD168, which were both up-regulated.…”

“…[43] Another decisive input could stem from astrocytes activated by the neoplastic lesion and the consequent up-regulation of matricellular proteins such as secreted protein acidic and rich in cys-teins (SPARC) in astrocytoma [44] and medulloblastoma [45] or connective tissue growth factor in glioma, [46] which jointly with additional matricellular proteins remodel neuronal tissue during development or after brain injury. [28] Significantly, the concept of reciprocal stimulation of tumor cells and astrocytes was recently also identified in metastatic melanoma, which elicits an inflammatory cytokine response in astrocytes that facilitates brain metastasis. [47] Combined, these studies emphasize the importance of incorporating environmental parameters into experimental protocols to explore their contribution to the proteomic landscape and the functional outcomes of primary brain tumors.…”