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Bone Nov 2015The development of the vertebrate skeleton reflects its evolutionary history. Cartilage formation came before biomineralization and a head skeleton evolved before the... (Review)
Review
The development of the vertebrate skeleton reflects its evolutionary history. Cartilage formation came before biomineralization and a head skeleton evolved before the formation of axial and appendicular skeletal structures. This review describes the processes that result in endochondral and intramembranous ossification, the important roles of growth and transcription factors, and the consequences of mutations in some of the genes involved. Following a summary of the origin of cartilage, muscle, and tendon cell lineages in the axial skeleton, we discuss the role of muscle forces in the formation of skeletal architecture and assembly of musculoskeletal functional units. Finally, ontogenetic patterning of bones in response to mechanical loading is reviewed.This article is part of a Special Issue entitled "Muscle Bone Interactions".
Topics: Animals; Bone Development; Chondrogenesis; Humans; Osteogenesis; Tendons; Transcription Factors
PubMed: 26453494
DOI: 10.1016/j.bone.2015.04.035 -
Differentiation; Research in Biological... 2016Mesenchymal stem cells (MSCs) are multipotent cells that represent a promising source for regenerative medicine. MSCs are capable of osteogenic, chondrogenic, adipogenic... (Review)
Review
Mesenchymal stem cells (MSCs) are multipotent cells that represent a promising source for regenerative medicine. MSCs are capable of osteogenic, chondrogenic, adipogenic and myogenic differentiation. Efficacy of differentiated MSCs to regenerate cells in the injured tissues requires the ability to maintain the differentiation toward the desired cell fate. Since MSCs represent an attractive source for autologous transplantation, cellular and molecular signaling pathways and micro-environmental changes have been studied in order to understand the role of cytokines, chemokines, and transcription factors on the differentiation of MSCs. The differentiation of MSC into a mesenchymal lineage is genetically manipulated and promoted by specific transcription factors associated with a particular cell lineage. Recent studies have explored the integration of transcription factors, including Runx2, Sox9, PPARγ, MyoD, GATA4, and GATA6 in the differentiation of MSCs. Therefore, the overexpression of a single transcription factor in MSCs may promote trans-differentiation into specific cell lineage, which can be used for treatment of some diseases. In this review, we critically discussed and evaluated the role of transcription factors and related signaling pathways that affect the differentiation of MSCs toward adipocytes, chondrocytes, osteocytes, skeletal muscle cells, cardiomyocytes, and smooth muscle cells.
Topics: Adipogenesis; Animals; Cell Differentiation; Chondrogenesis; Humans; Mesenchymal Stem Cells; Muscle Development; Regenerative Medicine; Transcription Factors
PubMed: 27012163
DOI: 10.1016/j.diff.2016.02.005 -
Development (Cambridge, England) Mar 2015Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from... (Review)
Review
Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation.
Topics: Animals; Chondrocytes; Chondrogenesis; Growth Plate; Humans; Transcription Factors
PubMed: 25715393
DOI: 10.1242/dev.105536 -
Science Advances Feb 2023Mesenchymal stem cell (MSC) chondrogenesis in three-dimensional (3D) culture involves dynamic changes in cytoskeleton architecture during mesenchymal condensation before...
Mesenchymal stem cell (MSC) chondrogenesis in three-dimensional (3D) culture involves dynamic changes in cytoskeleton architecture during mesenchymal condensation before morphogenesis. However, the mechanism linking dynamic mechanical properties of matrix to cytoskeletal changes during chondrogenesis remains unclear. Here, we investigated how viscoelasticity, a time-dependent mechanical property of collagen hydrogel, coordinates MSC cytoskeleton changes at different stages of chondrogenesis. The viscoelasticity of collagen hydrogel was modulated by controlling the gelling process without chemical cross-linking. In slower-relaxing hydrogels, although a disordered cortical actin promoted early chondrogenic differentiation, persistent myosin hyperactivation resulted in Rho-associated kinase (ROCK)-dependent apoptosis. Meanwhile, faster-relaxing hydrogels promoted cell-matrix interactions and eventually facilitated long-term chondrogenesis with mitigated myosin hyperactivation and cell apoptosis, similar to the effect of ROCK inhibitors. The current work not only reveals how matrix viscoelasticity coordinates MSC chondrogenesis and survival in a ROCK-dependent manner but also highlights viscoelasticity as a design parameter for biomaterials for chondrogenic 3D culture.
Topics: Hydrogels; Chondrogenesis; Collagen; Cell Differentiation; Mesenchymal Stem Cells; Cells, Cultured
PubMed: 36763657
DOI: 10.1126/sciadv.ade9497 -
Nature Communications Jan 2021The therapeutic application of human induced pluripotent stem cells (hiPSCs) for cartilage regeneration is largely hindered by the low yield of chondrocytes accompanied...
The therapeutic application of human induced pluripotent stem cells (hiPSCs) for cartilage regeneration is largely hindered by the low yield of chondrocytes accompanied by unpredictable and heterogeneous off-target differentiation of cells during chondrogenesis. Here, we combine bulk RNA sequencing, single cell RNA sequencing, and bioinformatic analyses, including weighted gene co-expression analysis (WGCNA), to investigate the gene regulatory networks regulating hiPSC differentiation under chondrogenic conditions. We identify specific WNTs and MITF as hub genes governing the generation of off-target differentiation into neural cells and melanocytes during hiPSC chondrogenesis. With heterocellular signaling models, we further show that WNT signaling produced by off-target cells is responsible for inducing chondrocyte hypertrophy. By targeting WNTs and MITF, we eliminate these cell lineages, significantly enhancing the yield and homogeneity of hiPSC-derived chondrocytes. Collectively, our findings identify the trajectories and molecular mechanisms governing cell fate decision in hiPSC chondrogenesis, as well as dynamic transcriptome profiles orchestrating chondrocyte proliferation and differentiation.
Topics: Animals; Benzeneacetamides; Cell Differentiation; Cell Line; Cells, Cultured; Chondrogenesis; Computational Biology; Gene Expression Profiling; Humans; Induced Pluripotent Stem Cells; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Pluripotent Stem Cells; Pyridines; Single-Cell Analysis; Transcriptome; Mice
PubMed: 33441552
DOI: 10.1038/s41467-020-20598-y -
Journal of Cellular and Molecular... Jun 2021Extracellular vesicles (EVs), mainly exosomes and microvesicles, are bilayer lipids containing biologically active information, including nucleic acids and proteins.... (Review)
Review
Extracellular vesicles (EVs), mainly exosomes and microvesicles, are bilayer lipids containing biologically active information, including nucleic acids and proteins. They are involved in cell communication and signalling, mediating many biological functions including cell growth, migration and proliferation. Recently, EVs have received great attention in the field of tissue engineering and regenerative medicine. Many in vivo and in vitro studies have attempted to evaluate the chondrogenesis potential of these microstructures and their roles in cartilage regeneration. EVs derived from mesenchymal stem cells (MSCs) or chondrocytes have been found to induce chondrocyte proliferation and chondrogenic differentiation of stem cells in vitro. Preclinical studies have shown that exosomes derived from MSCs have promising results in cartilage repair and in cell-free therapy of osteoarthritis. This review will focus on the in vitro and in vivo chondrogenesis and cartilage regeneration of EVs as well as their potential in the treatment of osteoarthritis.
Topics: Animals; Cartilage; Chondrogenesis; Extracellular Vesicles; Humans; Regenerative Medicine
PubMed: 33942981
DOI: 10.1111/jcmm.16290 -
Developmental Biology Jul 2020Initial limb chondrogenesis offers the first differentiated tissues that resemble the mature skeletal anatomy. It is a developmental progression of three tissues. The... (Review)
Review
Initial limb chondrogenesis offers the first differentiated tissues that resemble the mature skeletal anatomy. It is a developmental progression of three tissues. The limb begins with undifferentiated mesenchyme-1, some of which differentiates into condensations-2, and this tissue then transforms into cartilage-3. Each tissue is identified by physical characteristics of cell density, shape, and extracellular matrix composition. Tissue specific regimes of gene regulation underlie the diagnostic physical and chemical properties of these three tissues. These three tissue based regimes co-exist amid a background of other gene regulatory regimes within the same tissues and time-frame of limb development. The bio-molecular indicators of gene regulation reveal six identifiable patterns. Three of these patterns describe the unique bio-molecular indicators of each of the three tissues. A fourth pattern shares bio-molecular indicators between condensation and cartilage. Finally, a fifth pattern is composed of bio-molecular indicators that are found in undifferentiated mesenchyme prior to any condensation differentiation, then these bio-molecular indicators are upregulated in condensations and downregulated in undifferentiated mesenchyme. The undifferentiated mesenchyme that remains in between the condensations and cartilage, the interdigit, contains a unique set of bio-molecular indicators that exhibit dynamic behaviour during chondrogenesis and therefore argue for its own inclusion as a tissue in its own right and for more study into this process of differentiation.
Topics: Animals; Cartilage; Cell Differentiation; Chondrogenesis; Extracellular Matrix; Gene Expression Regulation, Developmental; Limb Buds; Mesoderm; Proteoglycans
PubMed: 32417169
DOI: 10.1016/j.ydbio.2020.04.009 -
Cellular & Molecular Biology Letters May 2023Deer antlers are the only known mammalian structure that undergoes full regeneration. In addition, it is peculiar because when growing, it contains vascularized...
BACKGROUND
Deer antlers are the only known mammalian structure that undergoes full regeneration. In addition, it is peculiar because when growing, it contains vascularized cartilage. The differentiation of antler stem cells (ASCs) into chondrocytes while inducing endochondral extension of blood vessels is necessary to form antler vascularized cartilage. Therefore, antlers provide an unparalleled opportunity to investigate chondrogenesis, angiogenesis, and regenerative medicine. A study found that Galectin-1 (GAL-1), which can be used as a marker in some tumors, is highly expressed in ASCs. This intrigued us to investigate what role GAL-1 could play in antler regeneration.
METHODS
We measured the expression level of GAL-1 in antler tissues and cells by immunohistochemistry, WB and QPCR. We constructed antlerogenic periosteal cells (APCs, one cell type of ASCs) with the GAL-1 gene knocked out (APC) using CRISPR-CAS9 gene editing system. The effect of GAL-1 on angiogenesis was determined by stimulating human umbilical vein endothelial cells (HUVECs) using APC conditioned medium or adding exogenous deer GAL-1 protein. The effect of APC on chondrogenic differentiation was evaluated compared with the APCs under micro-mass culture. The gene expression pattern of APC was analyzed by transcriptome sequencing.
RESULTS
Immunohistochemistry revealed that GAL-1 was widely expressed in the antlerogenic periosteum (AP), pedicle periosteum (PP) and antler growth center. Western blot and qRT-PCR analysis using deer cell lines further supports this result. The proliferation, migration, and tube formation assays of human umbilical vein endothelial cells (HUVECs) showed that the proangiogenic activity of APC medium was significantly decreased (P < 0.05) compared with the APCs medium. The proangiogenic activity of deer GAL-1 protein was further confirmed by adding exogenous deer GAL-1 protein (P < 0.05). The chondrogenic differentiation ability of APC was impeded under micro-mass culture. The terms of GO and KEGG enrichment of the differentially expressed genes (DEGs) of APC showed that down-regulated expression of pathways associated with deer antler angiogenesis, osteogenesis and stem cell pluripotency, such as the PI3K-AKT signaling pathway, signaling pathways regulating pluripotency of stem cells and TGF-β signaling pathway.
CONCLUSIONS
Deer GAL-1, has strong angiogenic activity, is widely and highly expressed in deer antler. The APCs can induce angiogenesis by secreting GAL-1. The knockout of GAL-1 gene of APCs damaged its ability to induce angiogenesis and differentiate into chondrocytes. This ability is crucial to the formation of deer antler vascularized cartilage. Moreover, Deer antlers offer a unique model to explore explore how angiogenesis at high levels of GAL-1 expression can be elegantly regulated without becoming cancerous.
Topics: Animals; Humans; Chondrogenesis; Antlers; Deer; Galectin 1; Phosphatidylinositol 3-Kinases; Endothelial Cells
PubMed: 37189051
DOI: 10.1186/s11658-023-00456-7 -
International Journal of Molecular... May 2023The search for innovative ways to treat osteoarthritis (OA) is an urgent task for molecular medicine and biogerontology. OA leads to disability in persons of middle and... (Review)
Review
The search for innovative ways to treat osteoarthritis (OA) is an urgent task for molecular medicine and biogerontology. OA leads to disability in persons of middle and older age, while safe and effective methods of treating OA have not yet been discovered. The directed differentiation of mesenchymal stem cells (MSCs) into chondrocytes is considered one of the possible methods to treat OA. This review describes the main molecules involved in the chondrogenic differentiation of MSCs. The peptides synthesized on the basis of growth factors' structures (SK2.1, BMP, B2A, and SSPEPS) and components of the extracellular matrix of cartilage tissue (LPP, CFOGER, CMP, RDG, and N-cadherin mimetic peptide) offer the greatest promise for the regulation of the chondrogenic differentiation of MSCs. These peptides regulate the WNT, ERK-p38, and Smad 1/5/8 signaling pathways, gene expression, and the synthesis of chondrogenic differentiation proteins such as COL2, SOX9, ACAN, etc.
Topics: Cartilage; Cell Differentiation; Chondrocytes; Extracellular Matrix; Peptides; Chondrogenesis; Cells, Cultured
PubMed: 37176122
DOI: 10.3390/ijms24098415 -
Journal of Cellular and Molecular... Jan 2022Different cellular and molecular mechanisms contribute to chondrocyte and osteocyte development. Although vital roles of the mothers against decapentaplegic homolog 4... (Review)
Review
Different cellular and molecular mechanisms contribute to chondrocyte and osteocyte development. Although vital roles of the mothers against decapentaplegic homolog 4 (also called 'SMAD4') have been discussed in different cancers and stem cell-related studies, there are a few reviews summarizing the roles of this protein in the skeletal development and bone homeostasis. In order to fill this gap, we discuss the critical roles of SMAD4 in the skeletal development. To this end, we review the different signalling pathways and also how SMAD4 defines stem cell features. We also elaborate how the epigenetic factors-ie DNA methylation, histone modifications and noncoding RNAs-make a contribution to the chondrocyte and osteocyte development. To better grasp the important roles of SMAD4 in the cartilage and bone development, we also review the genotype-phenotype correlation in animal models. This review helps us to understand the importance of the SMAD4 in the chondrocyte and bone development and the potential applications for therapeutic goals.
Topics: Animals; Cartilage; Cell Differentiation; Chondrocytes; Chondrogenesis; Osteocytes; Osteogenesis; Signal Transduction; Stem Cells
PubMed: 34841647
DOI: 10.1111/jcmm.17080