Laminin-Inspired Cell-Instructive Microenvironments for Neural Stem Cells

Abstract

Laminin is a heterotrimeric glycoprotein with a key role in the formation and maintenance of the basement membrane architecture and properties, as well as on the modulation of several biological functions, including cell adhesion, migration, differentiation and matrix-mediated signaling. In the central nervous system (CNS), laminin is differentially expressed during development and homeostasis, with an impact on the modulation of cell function and fate. Within neurogenic niches, laminin is one of the most important and well described extracellular matrix (ECM) proteins. Specifically, efforts have been made to understand laminin assembly, domain architecture, and interaction of its different bioactive domains with cell surface receptors, soluble signaling molecules, and ECM proteins, to gain insight into the role of this ECM protein and its receptors on the modulation of neurogenesis, both in homeostasis and during repair. This is also expected to provide a rational basis for the design of biomaterial-based matrices mirroring the biological properties of the basement membrane of neural stem cell niches, for application in neural tissue repair and cell transplantation. This review provides a general overview of laminin structure and domain architecture, as well as the main biological functions mediated by this heterotrimeric glycoprotein. The expression and distribution of laminin in the CNS and, more specifically, its role within adult neural stem cell niches is summarized. Additionally, a detailed overview on the use of full-length laminin and laminin derived peptide/recombinant laminin fragments for the development of hydrogels for mimicking the neurogenic niche microenvironment is given. Finally, the main challenges associated with the development of laminin-inspired hydrogels and the hurdles to overcome for these to progress from bench to bedside are discussed. Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 which is divided into five laminin globular (LG) domains (LG1-LG5) grouped into functional and structural distinct subdomains, LG1-3 and LG4 and LG5.(23) The coiled-coil is thought to help to orientate the LG domains so that they can be available to interact with cells via cell surface receptors, including...

A Hydrogel Platform that Incorporates Laminin Isoforms for Efficient Presentation of Growth Factors – Neural Growth and Osteogenesis

“…Results are reported in Figure 2B for PEG + SH and LM521/PEG + VPM gels with the same ratio AC:VPM (2:1). Variation of PEG-AC content at final concentration of 3.5, 5, 10, 12, and 15% w/v allowed us to produce a wide range of stiffnesses, from very soft gels suitable for 3D culture of neural cells, for example, ≈2 kPa for 3.5% w/v LM521/PEG degradable; [33,34,36,49] to stiff gels suitable for osteogenic differentiation of stem cells, for example, ≈25 kPa (and up to ≈80 kPa; Figure S3B, Supporting Information) for 15% w/v LM521/PEG degradable. [45,50] The low frequency range and LVE regime of the measurements explain the increase in E with polymer concentration as a direct consequence of the increasing number of crosslinks in the network, following rubber elasticity theory, [48] and in accordance with PEG gels reported in literature.…”

“…[9,[33][34][35] For example, hydrogels functionalized with fulllength LM111 take advantage of its multiple bioactive domains that bind components of the basal membrane such as nidogen, perlecan, agrin, and collagen IV to enhance nervous tissue regeneration (neurite growth and neural stem cell (NSC) differentiation). [33,[36][37][38][39][40] However, there are no studies that exploit the affinity of different GFs to various LM isoforms and their involvement in the organisation of different tissues. Moreover, LM may possess other domains that play a relevant role in the in vivo physiology of the cells, which cannot be mimicked in a short synthetic peptide and will still be functional when using the full-length protein.…”

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…An intracellular KS-PG, synaptic vesicle PG-2 (SV2), has important transmitter and storage properties for synaptic vesicle neurotransmitters. Perlecan and laminin-1 also have prominent roles to play via basement membrane structures in the regulation of neural outgrowth in the embryo through provision of an environment conducive to cell adhesion and cell migration [ 80 ]. A novel form of notochordal aggrecan substituted with HNK-1 trisaccharide guides neural crest progenitor cells during early stages of embryonic neural development [ 74 , 75 ].…”

Extracellular Matrix Proteins Confer Cell Adhesion-Mediated Drug Resistance Through Integrin αv in Glioblastoma Cells

“…are high-molecular-weight proteins of ECM and are thought as an important and biologically active part of basal lamina, influencing cell differentiation, migration, and adhesion (Yap et al, 2019;Barros et al, 2020). It is also documented that laminin was involved in the acquired chemotherapeutic resistance in gastric cancer (Sun et al, 2014).…”