Mechanics-Controlled Dynamic Cell Niches Guided Osteogenic Differentiation of Stem Cells via Preserved Cellular Mechanical Memory

Abstract

Stem cells sense and respond to their local dynamic mechanical niches, which further regulate the cellular behaviors. While in naturally, instead of instantly responding to real-time mechanical changes of their surrounding niches, stem cells often present a delayed cellular response over a time scale, namely cellular mechanical memory, which may finally influence their lineage choice. Here, we aim to build a dynamic mechanical niche model with alginate-based hydrogel, therein the dynamic mechanical switching can be easily realized via the introduce or removal of Ca2+. The results show that stiffening hydrogel (from soft to stiff) suppresses osteogenic differentiation of human mesenchymal stem cells (hMSCs) early on, though it finally promoted osteogenic differentiation over a long time period. Instead, softening hydrogel (from stiff to soft) still retains the strong osteogenic differentiation in the early days, though it finally showed a lower level of osteogenic differentiation compared with stiff hydrogel. Further, microRNA miR-21 has been found as a long-term mechanical memory sensor of the osteogenic program in hMSCs, as its level remains to match early mechanics of substrate over a period of time. Regulation of miR-21 level is efficient to erase the past mechanical memory and resensitize hMSCs to subsequent substrate mechanics. Our findings highlight cellular mechanical memory effect as a key factor of cell and cellular microenvironment interactions, which has been largely neglected before, and as a crucial design element of biomaterials for cell culture.

Pristine Gellan Gum–Collagen Interpenetrating Network Hydrogels as Mechanically Enhanced Anti-inflammatory Biologic Wound Dressings for Burn Wound Therapy

“…Although type-1 collagen is known to induce osteogenesis even under basal conditions, 33 previous studies suggested that the key precipitator in stem cell differentiation for hydrogel-based 3D culture is the bulk matrix stiffness. 34,35 Osteogenesis was only observed when the complex modulus of hydrogels is above 37 kPa. In contrast, the IPN hydrogel cannot be too soft as previous studies have suggested that only hydrogels with a storage modulus of >1600 Pa supported mechanotransduced cell adhesion.…”

Alteration of 3d Matrix Stiffness Regulates Viscoelasticity of Human Mesenchymal Stem Cells

“…This confounding parameter might interfere cell culture. Manipulation of miR-21 was proposed to erase this effect [28] but no references were available for execution under the circumstance of hMSCs osteogenesis. Second, the mechanical stimulus cultured hMSCs underwent depended on its posture.…”

Manipulation of Stem Cells Fates: The Master and Multifaceted Roles of Biophysical Cues of Biomaterials

“…Generally, biomaterial stiffness can be dynamically manipulated via stimulation with a magnet, [ 24a ] temperature, [ 18 ] crosslinking density, [ 28 ] ion concentration, [ 30 ] and pH. [ 31 ] For example, Wei et al.…”

“…created a dynamic hydrogel by immersing methacrylated alginate‐based hydrogel into CaCl 2 solution, in which the stiffness can be reversibly controlled via the introduction or removal of Ca 2+ from the hydrogel. [ 30 ]…”