Niche stiffness underlies the ageing of central nervous system progenitor cells

Abstract

Aging causes a decline in tissue regeneration due to a loss of function in adult stem and progenitor cell populations 1. An important example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs) 2. A relatively overlooked potential source for this loss of function is the stem cell niche, a source of cell-extrinsic cues including chemical and mechanical signalling 3,4. In this study, we show that the OPC microenvironment stiffens with age, and that this stiffening is sufficient to cause age-related OPC loss of function. Using biological and novel synthetic scaffolds to mimic the stiffness of young brain we find that isolated aged OPCs (aOPCs) cultured on these scaffolds are molecularly and functionally rejuvenated. When we Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

“…The most salient GO terms associated with this population were related to the cell surface and ECM, which is composed of proteoglycans such as chondroitin and heparin sulfate proteoglycans, and hyaluronan, as well as collagens, laminins, fibronectin, and tenascins (Gundelfinger, Frischknecht, Choquet, & Heine, ). Cells interact with their local environment through the presentation of plasma membrane proteins and secretion of specific ECM components, and the ECM reciprocally modulates OL‐lineage development through its mechanical‐structural properties and extensive chemical signaling network (Colognato & Tzvetanova, ; Segel et al, ). Interestingly, multiple chondroitin sulfate proteoglycans, including CSPG4, and VCAN, were expressed more highly in the pediatric l‐OPCs compared to the adult l‐OPCs.…”

“…Interestingly, multiple chondroitin sulfate proteoglycans, including CSPG4, and VCAN, were expressed more highly in the pediatric l‐OPCs compared to the adult l‐OPCs. In fact, it has been suggested that the scarcity of the ECM (Colognato & Tzvetanova, ) or the increase in ECM stiffness (Segel et al, ) associated with OL in the adult brain may be a contributing factor to its relatively poor capacity for remyelination. Gene products for secreted proteins that interact with and modify the functional properties of ECM were upregulated in l‐OPCs, including, the chemotropic guidance cues netrin‐1 (NTN1), semaphorins 5A and 5B (SEMA5A, SEMA5B), and SLIT1, as well as key receptor and downstream signaling components linked to these factors, including DSCAM, EPHB1, TRIO, CRMP1 and FYN (Brose & Tessier‐Lavigne, ; DeGeer et al, ; Fiore & Puschel, ; Henderson & Dalva, ; Lai Wing Sun, Correia, & Kennedy, ; Norris, Sundararajan, Morgan, Roberts, & Lundquist, ; Rajasekharan et al, ).…”

Fluctuation-Based Super-Resolution Traction Force Microscopy

“…The forces exerted by cells on their substrate can then be monitored as a function of bead movement within the gel. As the stiffness and the elastic modulus of the gel are pre-established, bead displacement can then, using mathematical equations, be converted into a read-out of local forces (Style et al, 2014).…”

“…The sensitivity and accuracy of TFM is directly linked to the ability to detect and track moving beads within a thick gel, and is generally limited to the detection of forces at the micron-scale (Roca-Cusachs et al, 2017;Style et al, 2014). As focal adhesions, the cellular structures involved in force generation and ECM remodelling, can be much smaller (Changede et al, 2019), there is a need to develop methods that can map cellular forces at high spatial resolution.…”

“…Classically, when performing TFM experiments, 200 nm fluorescent beads are embedded throughout the PAA gel (Style et al, 2014). This can result in substantial out-offocus light, which limits the use of widefield microscopes for TFM.…”