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Biomaterials directed in vivo osteogenic differentiation of mesenchymal cells derived from human embryonic stem cells.

ABSTRACT: Spontaneous differentiation of human embryonic stem cells (hESCs) is generally inefficient and leads to a heterogeneous population of differentiated and undifferentiated cells, limiting the potential use of hESCs for cell-based therapy and studies of specific differentiation programs. Here, we demonstrate biomaterial-dependent commitment of a mesenchymal cell population derived from hESCs toward the osteogenic lineage in vivo. In skeletal development, bone formation from condensing mesenchymal cells involves two distinct pathways: endochondral and intramembraneous bone formation. In this study, we demonstrate that the hESC-derived mesenchymal cells differentiate and regenerate in vivo bone tissues through two different pathways depending upon the local cues present in a scaffold microenvironment. Hydroxyapatite (HA) was incorporated into biodegradable poly(lactic-co-glycolic acid)/poly(l-lactic acid) (PLGA/PLLA) scaffolds to enhance bone formation. The HA microenvironment stabilized the β-catenin and upregulated Runx2, resulting in faster bone formation through intramembraneous ossification. hESC-derived mesenchymal cells seeded on the PLGA/PLLA scaffold without HA, however, showed minimal levels Runx2, and differentiated via endochondral ossification, as evidenced by formation of cartilaginous tissue, followed by calcification and increased blood vessel invasion. These results indicate that the ossification mechanisms of the hESC-derived mesenchymal stem cells can be regulated by the scaffold-mediated microenvironments, and bone tissue can be formed.

SUBMITTER: Hwang NS

PROVIDER: S-EPMC3699956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Combined macromolecule biomaterials together with fluid shear stress promote the osteogenic differentiation capacity of equine adipose-derived mesenchymal stem cells.

Project description:BackgroundCombination of mesenchymal stem cells (MSCs) and biomaterials is a rapidly growing approach in regenerative medicine particularly for chronic degenerative disorders including osteoarthritis and osteoporosis. The present study examined the effect of biomaterial scaffolds on equine adipose-derived MSC morphology, viability, adherence, migration, and osteogenic differentiation.MethodsMSCs were cultivated in conjunction with collagen CultiSpher-S Microcarrier (MC), nanocomposite xerogels B30 and combined B30 with strontium (B30Str) biomaterials in osteogenic differentiation medium either under static or mechanical fluid shear stress (FSS) culture conditions. The data were generated by histological means, live cell imaging, cell viability, adherence and migration assays, semi-quantification of alkaline phosphatase (ALP) activity, and quantification of the osteogenic markers runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) expression.ResultsThe data revealed that combined mechanical FSS with MC but not B30 enhanced MSC viability and promoted their migration. Combined osteogenic medium with MC, B30, and B30Str increased ALP activity compared to cultivation in basal medium. Osteogenic induction with MC, B30, and B30Str resulted in diffused matrix mineralization. The combined osteogenic induction with biomaterials under mechanical FSS increased Runx2 protein expression either in comparison to those cells cultivated in BM or those cells induced under static culture. Runx2 and ALP expression was upregulated following combined osteogenic differentiation together with B30 and B30Str regardless of static or FSS culture.ConclusionsTaken together, the data revealed that FSS in conjunction with biomaterials promoted osteogenic differentiation of MSCs. This combination may be considered as a marked improvement for clinical applications to cure bone defects.

| S-EPMC7879632 | biostudies-literature

Virus Nanoparticles Mediated Osteogenic Differentiation of Bone Derived Mesenchymal Stem Cells.

Project description:There are few methodologies that allow manipulating a biomaterial surface at nanometer scale, which controllably influence different cellular functions. In this study, virus nanoparticles with different structural features are selected to prepare 2D substrates with defined nanoscale topographies and the cellular responses are investigated. It is demonstrated that the viral nanoparticle based substrates could accelerate and enhance osteogenesis of bone derived mesenchymal stem cells as indicated by the upregulation of osteogenic markers, including bone morphogenetic protein-2, osteocalcin, and osteopontin, at both gene and protein expression levels. Moreover, alkaline phosphatase activity and calcium mineralization, both indicators for a -successful bone formation, are also increased in cells grown on these nanoscale possessed substrates. These discoveries and developments present a new paradigm for nanoscale engineering of a biomaterial surface.

| S-EPMC5115314 | biostudies-literature

Human amnion-derived mesenchymal stem cells promote osteogenic and angiogenic differentiation of human adipose-derived stem cells.

Project description:Tissue engineering using suitable mesenchymal stem cells (MSCs) shows great potential to regenerate bone defects. Our previous studies have indicated that human amnion-derived mesenchymal stem cells (HAMSCs) could promote the osteogenic differentiation of human bone marrow mesenchymal stem cells (HBMSCs). Human adipose-derived stem cells (HASCs), obtained from adipose tissue in abundance, are capable of multi-lineage differentiation. In this study, the effects of HAMSCs on osteogenic and angiogenic differentiation of HASCs were systematically investigated. Proliferation levels were measured by flow cytometry. Osteoblastic differentiation and mineralization were investigated using chromogenic alkaline phosphatase activity (ALP) activity substrate assays, Alizarin red S staining, real-time polymerase chain reaction (real-time PCR) analysis of osteogenic marker expression, and Western blotting. We found that HAMSCs increased the proliferation and osteoblastic differentiation of HASCs. Moreover, enzyme-linked immunosorbent assay (ELISA) and human umbilical vein endothelial cells (HUVECs) tube formation suggested HAMSCs enhanced angiogenic potential of HASCs via secretion of increased vascular endothelial growth factor (VEGF). Thus, we conclude that HAMSC might be a valuable therapeutic approach to promote HASCs-involved bone regeneration.

| S-EPMC5636128 | biostudies-literature

Engineering elastic bioactive composite hydrogels for promoting osteogenic differentiation of embryonic mesenchymal stem cells.

Project description:The development of bioactive materials with good mechanical properties and promotion of stem cell osteogenic differentiation has important application prospects in bone tissue engineering. In this paper, we designed a novel organic‒inorganic composite hydrogel (FPIGP@BGN-Sr) utilizing diacrylated F127 (DA-PF127), β-glycerophosphate-modified polyitaconate (PIGP) and strontium-doped bioactive glass nanoparticles (BGN-Sr) through free radical polymerization and coordination interactions and then evaluated its promoting effect on the osteogenic differentiation of mouse embryonic mesenchymal stem cells in detail. The results showed that the FPIGP@BGN-Sr hydrogel exhibited a controlled storage modulus by changing the amount of BGN-Sr. Notably, the FPIGP@BGN-Sr hydrogel possessed excellent elastic ability with a compressive strain of up to 98.6% and negligible change in mechanical properties after 10 cycles of compression. In addition, the FPIGP@BGN-Sr hydrogel had good cytocompatibility, maintained the activity and proliferation of mouse embryonic mesenchymal stem cells (C3H10T1/2), and effectively enhanced the activity of alkaline phosphatase, osteogenic gene expression and biomineralization ability of the cells. In conclusion, the excellent mechanical properties and osteogenic biological activity of the FPIGP@BGN-Sr hydrogel make it a promising organic‒inorganic composite bioactive material for stem cell-based bone regeneration.

| S-EPMC9596812 | biostudies-literature

MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo.

Project description:Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85%, and conversely, in vivo bone formation was enhanced by 60% when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3' UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.

| S-EPMC3076836 | biostudies-other

The effects of secretion factors from umbilical cord derived mesenchymal stem cells on osteogenic differentiation of mesenchymal stem cells.

Project description:Factors synthesized by mesenchymal stem cells (MSCs) contain various growth factors, cytokines, exosomes and microRNAs, which may affect the differentiation abilities of MSCs. In the present study, we investigated the effects of secretion factors of human umbilical cord derived mesenchymal stem cells (hUCMSCs) on osteogenesis of human bone marrow derived MSCs (hBMSCs). The results showed that 20 μg/ml hUCMSCs secretion factors could initiate osteogenic differentiation of hBMSCs without osteogenic induction medium (OIM), and the amount of calcium deposit (stained by Alizarin Red) was significantly increased after the hUCMSCs secretion factors treatment. Real time quantitative reverse transcription-polymerase chain reaction (real time qRT-PCR) demonstrated that the expression of osteogenesis-related genes including ALP, BMP2, OCN, Osterix, Col1α and Runx2 were significantly up-regulated following hUCMSCs secretion factors treatment. In addition, we found that 10 μg hUCMSCs secretion factors together with 2×10(5) hBMSCs in the HA/TCP scaffolds promoted ectopic bone formation in nude mice. Local application of 10 μg hUCMSCs secretion factors with 50 μl 2% hyaluronic acid hydrogel and 1×10(5) rat bone marrow derived MSCs (rBMSCs) also significantly enhanced the bone repair of rat calvarial bone critical defect model at both 4 weeks and 8 weeks. Moreover, the group that received the hUCMSCs secretion factors treatment had more cartilage and bone regeneration in the defect areas than those in the control group. Taken together, these findings suggested that hUCMSCs secretion factors can initiate osteogenesis of bone marrow MSCs and promote bone repair. Our study indicates that hUCMSCs secretion factors may be potential sources for promoting bone regeneration.

| S-EPMC4370627 | biostudies-literature

Lamc1 promotes osteogenic differentiation and inhibits adipogenic differentiation of bone marrow-derived mesenchymal stem cells.

Project description:Bone marrow-derived mesenchymal stem cells (BMSCs) exhibit multi-lineage differentiation potential and robust proliferative capacity. The late stage of differentiation signifies the functional maturation and characterization of specific cell lineages, which is crucial for studying lineage-specific differentiation mechanisms. However, the molecular processes governing late-stage BMSC differentiation remain poorly understood. This study aimed to elucidate the key biological processes involved in late-stage BMSC differentiation. Publicly available transcriptomic data from human BMSCs were analyzed after approximately 14 days of osteogenic, adipogenic, and chondrogenic differentiation. Thirty-one differentially expressed genes (DEGs) associated with differentiation were identified. Pathway enrichment analysis indicated that the DEGs were involved in extracellular matrix (ECM)-receptor interactions, focal adhesion, and glycolipid biosynthesis, a ganglion series process. Subsequently, the target genes were validated using publicly available single-cell RNA-seq data from mouse BMSCs. Lamc1 exhibited predominant distribution in adipocytes and osteoblasts, primarily during the G2/M phase. Tln2 and Hexb were expressed in chondroblasts, osteoblasts, and adipocytes, while St3gal5 was abundantly distributed in stem cells. Cell communication analysis identified two receptors that interact with LAMCI. q-PCR results confirmed the upregulation of Lamc1, Tln2, Hexb, and St3gal5 during osteogenic differentiation and their downregulation during adipogenic differentiation. Knockdown of Lamc1 inhibited adipogenic and osteogenic differentiation. In conclusion, this study identified four genes, Lamc1, Tln2, Hexb, and St3gal5, that may play important roles in the late-stage differentiation of BMSCs. It elucidated their interactions and the pathways they influence, providing a foundation for further research on BMSC differentiation.

| S-EPMC11344058 | biostudies-literature

Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells.

Project description:Terminal differentiation of multipotent stem cells is achieved through a coordinated cascade of activated transcription factors and epigenetic modifications that drive gene transcription responsible for unique cell fate. Within the mesenchymal lineage, factors such as RUNX2 and PPAR? are indispensable for osteogenesis and adipogenesis, respectively. We therefore investigated genomic binding of transcription factors and accompanying epigenetic modifications that occur during osteogenic and adipogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (MSCs). As assessed by ChIP-sequencing and RNA-sequencing analyses, we found that genes vital for osteogenic identity were linked to RUNX2, C/EBP?, retinoid X receptor, and vitamin D receptor binding sites, whereas adipocyte differentiation favored PPAR?, retinoid X receptor, C/EBP?, and C/EBP? binding sites. Epigenetic marks were clear predictors of active differentiation loci as well as enhancer activities and selective gene expression. These marrow-derived MSCs displayed an epigenetic pattern that suggested a default preference for the osteogenic pathway; however, these patterns were rapidly altered near the Adipoq, Cidec, Fabp4, Lipe, Plin1, Pparg, and Cebpa genes during adipogenic differentiation. Surprisingly, we found that these cells also exhibited an epigenetic plasticity that enabled them to trans-differentiate from adipocytes to osteoblasts (and vice versa) after commitment, as assessed by staining, gene expression, and ChIP-quantitative PCR analysis. The osteogenic default pathway may be subverted during pathological conditions, leading to skeletal fragility and increased marrow adiposity during aging, estrogen deficiency, and skeletal unloading. Taken together, our data provide an increased mechanistic understanding of the epigenetic programs necessary for multipotent differentiation of MSCs that may prove beneficial in the development of therapeutic strategies.

| S-EPMC5016174 | biostudies-literature

SIRT6 Promotes Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells Through Antagonizing DNMT1.

Project description:BackgroundAdipose-derived stem cells (ADSCs) are increasingly used in regenerative medicine because of their potential to differentiate into multiple cell types, including osteogenic lineages. Sirtuin protein 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that plays important roles in cell differentiation. NOTCH signaling has also been reported to involve in osteogenic differentiation. However, the function of SIRT6 in osteogenic differentiation of ADSCs and its relation to the NOTCH signaling pathways are yet to be explored.MethodsThe in vitro study with human ADSCs (hADSCs) and in vivo experiments with nude mice have been performed. Alkaline phosphatase (ALP) assays and ALP staining were used to detect osteogenic activity. Alizarin Red staining was performed to detect calcium deposition induced by osteogenic differentiation of ADSCs. Western blot, RT-qPCR, luciferase reporter assay, and co-immunoprecipitation assay were applied to explore the relationship between of SIRT6, DNA methyltransferases (DNMTs) and NOTCHs.ResultsSIRT6 promoted ALP activity, enhanced mineralization and upregulated expression of osteogenic-related genes of hADSCs in vitro and in vivo. Further mechanistic studies showed that SIRT6 deacetylated DNMT1, leading to its unstability at protein level. The decreased expression of DNMT1 prevented the abnormal DNA methylation of NOTCH1 and NOTCH2, resulting in the upregulation of their transcription. SIRT6 overexpression partially suppressed the abnormal DNA methylation of NOTCH1 and NOTCH2 by antagonizing DNMT1, leading to an increased capacity of ADSCs for their osteogenic differentiation.ConclusionThis study demonstrates that SIRT6 physical interacts with the DNMT1 protein, deacetylating and destabilizing DNMT1 protein, leading to the activation of NOTCH1 and NOTCH2, Which in turn promotes the osteogenic differentiation of ADSCs.

| S-EPMC8258422 | biostudies-literature

Lipid nanoparticle-mediated silencing of osteogenic suppressor GNAS leads to osteogenic differentiation of mesenchymal stem cells in vivo.

Project description:Approved drugs for the treatment of osteoporosis can prevent further bone loss but do not stimulate bone formation. Approaches that improve bone density in metabolic diseases are needed. Therapies that take advantage of the ability of mesenchymal stem cells (MSCs) to differentiate into various osteogenic lineages to treat bone disorders are of particular interest. Here we examine the ability of small interfering RNA (siRNA) to enhance osteoblast differentiation and bone formation by silencing the negative suppressor gene GNAS in bone MSCs. Using clinically validated lipid nanoparticle (LNP) siRNA delivery systems, we show that silencing the suppressor gene GNAS in vitro in MSCs leads to molecular and phenotypic changes similar to those seen in osteoblasts. Further, we demonstrate that these LNP-siRNAs can transfect a large proportion of mice MSCs in the compact bone following intravenous injection. Transfection of MSCs in various animal models led to silencing of GNAS and enhanced differentiation of MSCs into osteoblasts. These data demonstrate the potential for LNP delivery of siRNA to enhance the differentiation of MSCs into osteoblasts, and suggests that they are a promising approach for the treatment of osteoporosis and other bone diseases.

| S-EPMC9481989 | biostudies-literature

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