Molecular Engineering of Pericellular Microniche via Biomimetic Proteoglycans Modulates Cell Mechanobiology

Abstract

Molecular engineering of biological tissues using synthetic mimics of native matrix molecules can modulate the mechanical properties of the cellular microenvironment through physical interactions with existing matrix molecules, and in turn, mediate the corresponding cell mechanobiology. In articular cartilage, the pericellular matrix (PCM) is the immediate microniche that regulates cell fate, signaling, and metabolism. The negatively charged osmo-environment, as endowed by PCM proteoglycans, is a key biophysical cue for cell mechanosensing. This study demonstrated that biomimetic proteoglycans (BPGs), which mimic the ultrastructure and polyanionic nature of native proteoglycans, can be used to molecularly engineer PCM micromechanics and cell mechanotransduction in cartilage. Upon infiltration into bovine cartilage explant, we showed that localization of BPGs in the PCM leads to increased PCM micromodulus and enhanced chondrocyte intracellular calcium signaling. Applying molecular force spectroscopy, we revealed that BPGs integrate with native PCM through augmenting the molecular adhesion of aggrecan, the major PCM proteoglycan, at the nanoscale. These interactions are enabled by the biomimetic “bottle-brush” ultrastructure of BPGs and facilitate the integration of BPGs within the PCM. Thus, this class of biomimetic molecules can be used for modulating molecular interactions of pericellular proteoglycans and harnessing cell mechanosensing. Because the PCM is a prevalent feature of various cell types, BPGs hold promising potential for improving regeneration and disease modification for not only cartilage-related healthcare but many other tissues and diseases.

Molecular polymer bottlebrushes in nanomedicine: therapeutic and diagnostic applications

“…190 MPB gels can be used as injectable hydrogels for cancer immunochemotherapy 191 or directly injected as nonleaching tissue-mimetic elastomers for reconstructive surgery. 192 MPBs can further be used to yield structural analogues of proteoglycan aggregates, [193][194][195] a key component of cartilage, which may further prove valuable for the tissue engineering field. With shaped nanomaterials an ongoing a focus, strategies to induce and explore size-/shape-changing materials are in demand.…”

Preclinical and clinical orthotopic transplantation of decellularized/engineered tracheal scaffolds: A systematic literature review

“… 70 , 71 In addition, the microenvironment also plays a pivotal regulative role toward mechanosensitive cellular activities (i.e. adhesion, migration, solute transport, mechanotransduction), 72 in turn exerting a fundamental role whether considering scaffold repopulation. According to these evidences, the arrangement of the acellular trachea ultrastructure, monitored by SEM, was advised by some Authors.…”

Hierarchically patterned protein scaffolds with nano-fibrillar and micro-lamellar structures modulate neural stem cell homing and promote neuronal differentiation

“…The extracellular matrix (ECM) is a 3D network-like nanofibrous structure mainly formed by collagens, which plays a crucial role in maintaining cell morphology and regulating the fate of NSCs. Pieces of evidence suggest that biophysical cues provided by ECM-like 3D biomaterials can influence the cellular behavior of seeded cells, including cell recruit-ment, 15 cell infiltration, 16,17 and regulation of stem cell differentiation. [18][19][20] Biomacromolecules such as collagen and hyaluronic acid (HA) have become widely used biomaterials due to their good biocompatibility; however, they also suffer from low mechanical properties and rapid degradation rates.…”