Osteoarthritis (OA) is a degenerative disease that affects various tissues surrounding joints such as articular cartilage, subchondral bone, synovial membrane, and ligaments. No therapy is currently available to completely prevent the initiation or progression of the disease partly due to poor understanding of the mechanisms of the disease pathology. Cartilage is the main tissue afflicted by OA, and chondrocytes, the sole cellular component in the tissue, actively participate in the degeneration process. Multiple factors affect the development and progression of OA including inflammation that is sustained during the progression of the disease and alteration in biomechanical conditions due to wear and tear or trauma in cartilage. During the progression of OA, extracellular matrix (ECM) of cartilage is actively remodeled by chondrocytes under inflammatory conditions. This alteration of ECM, in turn, changes the biomechanical environment of chondrocytes, which further drives the progression of the disease in the presence of inflammation. The changes in ECM composition and structure also prevent participation of mesenchymal stem cells in the repair process by inhibiting their chondrogenic differentiation. This review focuses on how inflammation-induced ECM remodeling disturbs cellular activities to prevent self-regeneration of cartilage in the pathology of OA.

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Biomechanical forces have been shown to significantly affect tissue development, morphogenesis, pathogenesis and healing, especially in orthopaedic tissues. Such biological processes are critically related to the differentiation of human mesenchymal stem cells (hMSCs). However, the mechanistic details regarding how mechanical forces direct MSC This article is protected by copyright. All rights reserved. were upregulated in response to the increased magnitudes of compressive strain, whereas osteogenic markers (COL1A1, SPARC, RUNX2) and calcium deposition had noticeable decreases by compressive loading in a magnitude-dependent manner. Dynamic mechanical analysis showed enhanced viscoelastic modulus with respect to the increased dynamic strain peaking at 15%, which coincides with the maximal GAG synthesis. Furthermore, polarization-sensitive optical coherence tomography (PS-OCT) revealed that mechanical loading enhanced the alignment of extracellular matrix to the greatest level by 15% strain as well. Overall, we show that the degree of differentiation of hMSCs towards osteogenic or chondrogenic lineage is inversely related, and it depends on the magnitude of dynamic compressive strain. These results demonstrate that multi-phenotypic differentiation of hMSCs can be controlled by varying the strain regimens, providing a novel strategy to modulate differentiation specification and tissue morphogenesis.

Genetically modified bone marrow derived mesenchymal stem cells (MSCs) have proven to be efficient cell carriers for local or systemic delivery of therapeutics as well as for growth factors to augment tissue formation. However, efficient non-viral gene transfer to these cells is limiting their applicability. Although most studies focus on designing more efficient condensation agents for DNA, our focus in this manuscript is to study the role of two extracellular matrix proteins on the ability of MSCs to become transfected, collagen I (Col I) and fibronectin (Fn). Here we report that plating MSCs on Col I-coated surfaces inhibits transfection, while plating MSCs on Fn-coated surfaces enhances transfection. The mechanism by which these ECM proteins affect non-viral gene transfer involves the endocytosis pathway used for polyplex uptake and intracellular tension. We found that Fn promoted internalization through clathrin-mediated endocytosis and that this pathway resulted in more efficient transfection than caveolae-mediated endocytosis and macropinocytosis. Further, the disruption of actin-myosin interactions resulted in an enhancement of gene transfer for cells plated on Fn coated surfaces, but not for cells plated on Col I. We believe that the cellular microenvironment can be engineered to enhance the ability of cells to become transfected and that through understanding the mechanisms by which the ECM affects non-viral gene transfer, better materials and transfection protocols can be realized.

BackgroundTo maximize the translational utility of human induced pluripotent stem cells (iPSCs), the ability to precisely modulate the differentiation of iPSCs to target phenotypes is critical. Although the effects of the physical cell niche on stem cell differentiation are well documented, current approaches to direct step-wise differentiation of iPSCs have been typically limited to the optimization of soluble factors. In this regard, we investigated how temporally varied substrate stiffness affects the step-wise differentiation of iPSCs towards various lineages/phenotypes.MethodsElectrospun nanofibrous substrates with different reduced Young’s modulus were utilized to subject cells to different mechanical environments during the differentiation process towards representative phenotypes from each of three germ layer derivatives including motor neuron, pancreatic endoderm, and chondrocyte. Phenotype-specific markers of each lineage/stage were utilized to determine differentiation efficiency by reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence imaging for gene and protein expression analysis, respectively.ResultsThe results presented in this proof-of-concept study are the first to systematically demonstrate the significant role of the temporally varied mechanical microenvironment on the differentiation of stem cells. Our results demonstrate that the process of differentiation from pluripotent cells to functional end-phenotypes is mechanoresponsive in a lineage- and differentiation stage-specific manner.ConclusionsLineage/developmental stage-dependent optimization of electrospun substrate stiffness provides a unique opportunity to enhance differentiation efficiency of iPSCs for their facilitated therapeutic applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0667-2) contains supplementary material, which is available to authorized users.