Exploiting Heparan Sulfate Proteoglycans in Human Neurogenesis—Controlling Lineage Specification and Fate

Abstract

Unspecialized, self-renewing stem cells have extraordinary application to regenerative medicine due to their multilineage differentiation potential. Stem cell therapies through replenishing damaged or lost cells in the injured area is an attractive treatment of brain trauma and neurodegenerative neurological disorders. Several stem cell types have neurogenic potential including neural stem cells (NSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs). Currently, effective use of these cells is limited by our lack of understanding and ability to direct lineage commitment and differentiation of neural lineages. Heparan sulfate proteoglycans (HSPGs) are ubiquitous proteins within the stem cell microenvironment or niche and are found localized on the cell surface and in the extracellular matrix (ECM), where they interact with numerous signaling molecules. The glycosaminoglycan (GAG) chains carried by HSPGs are heterogeneous carbohydrates comprised of repeating disaccharides with specific sulfation patterns that govern ligand interactions to numerous factors including the fibroblast growth factors (FGFs) and wingless-type MMTV integration site family (Wnts). As such, HSPGs are plausible targets for guiding and controlling neural stem cell lineage fate. In this review, we provide an overview of HSPG family members syndecans and glypicans, and perlecan and their role in neurogenesis. We summarize the structural changes and subsequent functional implications of heparan sulfate as cells undergo neural lineage differentiation as well as outline the role of HSPG core protein expression throughout mammalian neural development and their function as cell receptors and co-receptors. Finally, we highlight suitable biomimetic approaches for exploiting the role of HSPGs in mammalian neurogenesis to control and tailor cell differentiation into specific lineages. An improved ability to control stem cell specific neural lineage fate and produce abundant cells of lineage specificity will further advance stem cell therapy for the development of improved repair of neurological disorders. We propose a deeper understanding of HSPG-mediated neurogenesis can potentially provide novel therapeutic targets of neurogenesis.

Tempora: cell trajectory inference using time-series single-cell RNA sequencing data

“…These patterns are consistent with the known proliferation of neural progenitors at the beginning of neurogenesis 24 and neuronal activities of newborn neurons later in the process 25 . Tempora also identifies more subtle changes in signaling pathways over time, such as the early enrichment of Insulin-like growth factor signaling and the later upregulation of Syndecan-3 mediated signaling, both of which are consistent with their known roles in early neurogenesis and neural circuit assembly, respectively [26][27][28] (Figure 3b…”

Culturing Adult Stem Cells for Cell-Based Therapeutics: Neuroimmune Applications

“…Moreover, FM19G11 induces self-renewal by inducing insulin-like signaling pathway and inducing ATP accumulation, activated glucose metabolism with glucose uptake by upregulation of the GLUT4 transporter. The over-induction of AKT/mTOR signaling was directly correlated to the FM19G11-dependent induction of the self-renewal-related markers Sox2, Oct4, Nanog, and Notch1 [130]. Interestingly, the use of a combination of FM19G11 treatment and epSPC transplantation for SCI therapy reduced the glial scar extension and increased the number of neuronal fibers at the epicenter of the lesion.…”

“…Nevertheless, the data sustains that MSCs may provide an abundant source that can be manipulated for purposes of neural repair and regeneration. Biomimetic approaches to exploit the role of HSPGs in neurogenesis, such as synthetic glycopolymers or heparin conjugates, are being developed so that neural differentiation into specific lineages can be controlled and tailored [96,130].…”

Estudo temporal integrado de redes de co-expressão gênica e microRNAs em um modelo experimental de convulsão febril induzida por hipertermia

“…O hub Mtss1 regula o crescimento de neuritos [Yu et al, 2016]. O gene Sdc1 atua na proliferação e manutenção de células progenitoras neurais [Wang et al, 2012] e está relacionado à via Wnt [Yu et al, 2017], importante no processo de epileptogênese na epilepsia do lobo temporal [Huang et al, 2015]. O hub Pycr1 está associado ao desenvolvimento neural e à autofagia [Zaki et al, 2016].…”

“…Crebl2 e Sdc1 [Ma et al, 2015;Yu et al, 2017]. E, por fim, o módulo blue apresenta hubs fortemente associados a características distintivas da epilepsia, como convulsões, resistência a drogas anticonvulsivantes e atividade do inflamassoma, respectivamente, com os hubs Nlpr3 e Adora2a, Kctd e Gpsm3 [Van Bogaert et al, 2007;Shinohara et al, 2013;Giguère et al, 2014;Meng et al, 2014].…”