Proliferation Of Marrow Mesenchymal Stem Cells Research Articles

Icariin accelerates bone regeneration by inducing osteogenesis-angiogenesis coupling in rats with type 1 diabetes mellitus

BACKGROUND Icariin (ICA), a natural flavonoid compound monomer, has multiple pharmacological activities. However, its effect on bone defect in the context of type 1 diabetes mellitus (T1DM) has not yet been examined. AIM To explore the role and potential mechanism of ICA on bone defect in the context of T1DM. METHODS The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis. A bone defect model was established in T1DM rats. The model rats were then treated with ICA or placebo and micron-scale computed tomography, histomorphometry, histology, and sequential fluorescent labeling were used to evaluate the effect of ICA on bone formation in the defect area. RESULTS ICA promoted bone marrow mesenchymal stem cell (BMSC) proliferation and osteogenic differentiation. The ICA treated-BMSCs showed higher expression levels of osteogenesis-related markers (alkaline phosphatase and osteocalcin) and angiogenesis-related markers (vascular endothelial growth factor A and platelet endothelial cell adhesion molecule 1) compared to the untreated group. ICA was also found to induce osteogenesis-angiogenesis coupling of BMSCs. In the bone defect model T1DM rats, ICA facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation. Lastly, ICA effectively accelerated the rate of bone formation in the defect area. CONCLUSION ICA was able to accelerate bone regeneration in a T1DM rat model by inducing osteogenesis-angiogenesis coupling of BMSCs.

Polysaccharide hybrid scaffold encapsulated endogenous factors for microfracture enhancement by sustainable release and cell recruitment

Autologous matrix-induced chondrogenesis improves microfracture (MF), but the lack of functional cells and factors inhibit a curative effect. Here, inspired by the healing process of wounds, we prepared a polysaccharide hybrid scaffold (HDCP) to immobilize endogenous growth factors (eGFs), which were derived from platelet-rich plasma (PRP). Compared with the absence of PRP, the hybrid cross-linking network endowed this scaffold with a denser pore structure, enhanced mechanical properties, and slower protein mass transfer rate, thus ensuring the long-term sustainable release of eGFs. In vitro studies confirmed that HDCP promoted bone marrow mesenchymal stem cell recruitment, proliferation, and chondrogenic differentiation. In vivo implantation indicated that HDCP regenerated a smooth articular cartilage surface with a regular fibrous matrix arrangement structure, and the mechanical strength of the regenerated cartilage considerably improved. The obvious MF enhancement implied that PRP and polysaccharide scaffold hybridization could be used as an implantable matrix for cartilage repair.

In vitro evaluation of BMSCs early proliferation on minocycline-loaded electrospun nanofibers membrane.

Electrospun nanofibers could simulate the natural extracellular matrix (ECM) of the host bone, while minocycline (MINO) is a broad-spectrum tetracycline antibiotic which has been found to have multiple non-antibiotics biological effects that promotes osteogenesis in vitro and in vivo. The present study aims at constructing a polylactic acid (PLA) electrospun nanofiber membrane loaded with MINO to enhance Bone marrow mesenchymal stem cells (BMSCs) adhesion and proliferation for early clinical treatment. The MINO-PLA membrane were characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR) and in vitro drug release study. The antibacterial ability was also investigated. In addition, in vitro cellular proliferation experiment was performed to verify whether the PLA electrospun nanofibers membrane loaded with MINO enhance BMSCs adhesion and proliferation. Analyzing the drug release and cell growth results, it was found that only the effective concentration of MINO-PLA could help the growth of BMSCs in the short term. This is related to the drug release rate of MINO-PLA and the initial concentration of MINO. This study shows that by controlling the concentration and release rate of MINO with electrospinning PLA, BMSCs could proliferate on it, and a new bone repair material had been made in this study.

A novel degradable PCL/PLLA strapping band for internal fixation of fracture

Early fracture fixation is the critical factor in fracture healing. Common internal fracture implants are made of metallic materials, which often affects the imaging quality of CT and MRI. Most patients will choose secondary surgery to remove the internal fixation implants, which causes secondary damage to them. The development of new degradable internal fracture implants has attracted more and more attention from orthopedic surgeons and researchers. Based on these problems, we improved the various properties of medical grade polycaprolactone (PCL) by adding poly(L-lactide) (PLLA). We produced PCL/PLLA strapping bands with different mass ratios by injection molding. We compared the mechanical properties, degradation properties, cell biocompatibility, bone marrow mesenchymal stem cells (BMSCs) adhesion, proliferation, osteogenic differentiation and fracture fixation effect of these strapping bands. The results showed that the tensile strength and yield force of the strapping bands increased with the increase of the content of PLLA. The addition of PLLA could significantly improve the mechanical strength in the early stage and accelerate the degradation rate of the strapping band. PCL/PLLA (80/20) strapping band had no significant cytotoxicity toward rBMSCs and could promote osteogenic differentiation of rBMSCs. The strapping band could ensure femoral fracture healing of beagles in 3 months and didn’t cause damage to the surrounding tissues and main organs. This study will provide some new insights into the biodegradable products of PCL/PLLA blends for internal fixation of fracture.Graphical We produced novel degradable PCL/PLLA strapping bands with different mass ratios by injection molding. We tested the biological safety of the prepared internal fixation strapping bands for fracture, such as cell experiment in vitro and animal experiment, and studied the degradation behavior in vitro. The strapping bands could ensure femoral fracture healing of beagles. This study will provide some new insights into the biodegradable products of PCL/PLLA blends for internal fixation of fracture. A Immunofluorescence staining of rBMSCs (live cells: green; dead cells: red). B Young’s modulus change curve during strapping bands degradation. C The implantation process of strapping bands. D Micro-CT images of the beagle’s fracture recovery after the operation.

Neodymium and manganese ions co-doped whitlockite for temperature monitoring, photothermal therapy, and bone tissue repair in osteosarcoma

Osteosarcoma is one of the most dangerous forms of tumors, leading to death in >90% of patients. The surgical treatment of osteosarcoma results in significant bone defects and risks of tumor recurrence. Using neodymium (Nd) and manganese (Mn) ions co-doped with whitlockite nanoparticle (Nd10%Mn10%WH NPs) and sodium alginate (SA), we designed and synthesized an organic–inorganic composite hydrogel (Nd10%Mn10%WH-SA) that displayed the excellent fluorescence and photothermal properties. Furthermore, the maximum fluorescence emission intensity of Nd10%Mn10%WH-SA at 1062 nm was linear with temperature. The optimal temperature for the treatment of tumors was determined by considering the changes in fluorescence intensity that led to a reduction in tissue damage around the tumors. Nd10%Mn10%WH NPs demonstrated a significant function in promoting human bone marrow mesenchymal stem cells (hBMSCs) proliferation. Furthermore, Nd10%Mn10%WH-SA could almost kill tumors when the photothermal temperature was raised to 50 °C, with a minimal leftover scar after photothermal therapy (PTT). Nd10%Mn10%WH-SA had a better promotion effect on the growth of the new bone. These results suggested that Nd10%Mn10%WH-SA offers a new PTT method for the “integrated treatment and repair” of osteosarcoma.

Flexible Fabrication and Hybridization of Bioactive Hydrogels with Robust Osteogenic Potency.

Osteogenic scaffolds reproducing the natural bone composition, structures, and properties have represented the possible frontier of artificially orthopedic implants with the great potential to revolutionize surgical strategies against the bone-related diseases. However, it is difficult to achieve an all-in-one formula with the simultaneous requirement of favorable biocompatibility, flexible adhesion, high mechanical strength, and osteogenic effects. Here in this work, an osteogenic hydrogel scaffold fabricated by inorganic-in-organic integration between amine-modified bioactive glass (ABG) nanoparticles and poly(ethylene glycol) succinimidyl glutarate-polyethyleneimine (TSG-PEI) network was introduced as an all-in-one tool to flexibly adhere onto the defective tissue and subsequently accelerate the bone formation. Since the N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG polymer could quickly react with the NH2-abundant polyethyleneimine (PEI) polymer and ABG moieties, the TSG-PEI@ABG hydrogel was rapidly formed with tailorable structures and properties. Relying on the dense integration between the TSG-PEI network and ABG moieties on a nano-scale level, this hydrogel expressed powerful adhesion to tissue as well as durable stability for the engineered scaffolds. Therefore, its self-endowed biocompatibility, high adhesive strength, compressive modulus, and osteogenic potency enabled the prominent capacities on modulation of bone marrow mesenchymal stem cell (BMSCs) proliferation and differentiation, which may propose a potential strategy on the simultaneous scaffold fixation and bone regeneration promotion for the tissue engineering fields.

Nanofiber Composite Microchannel-Containing Injectable Hydrogels for Cartilage Tissue Regeneration.

Articular cartilage tissue is incapable of self-repair and therapies for cartilage defects are still lacking. Injectable hydrogels have drawn much attention in the field of cartilage regeneration. Herein, the novel design of nanofiber composite microchannel-containing hydrogels inspired by the tunnel-piled structure of subway tunnels is proposed. Based on the aldehydized polyethylene glycol/carboxymethyl chitosan (APA/CMCS) hydrogels, thermosensitive gelatin microrods (GMs) are used as a pore-forming agent, and coaxial electrospinning polylactic acid/gelatin fibers (PGFs) loaded with kartogenin (KGN) are used as a reinforcing agent and a drug delivery system to construct the nanofiber composite microchannel-containing injectable hydrogels (APA/CMCS/KGN@PGF/GM hydrogels). The in situ formation, micromorphology and porosity, swelling and degradation, mechanical properties, self-healing behavior, as well as drug release of the nanofiber composite microchannel-containing hydrogels are investigated. The hydrogel exhibits good self-healing ability, and the introduction of PGF nanofibers can significantly improve the mechanical properties. The drug delivery system can realize sustained release of KGN to match the process of cartilage repair. The microchannel structure effectively promotes bone marrow mesenchymal stem cell (BMSC) proliferation and ingrowth within the hydrogels. In vitro and animal experiments indicate that the APA/CMCS/KGN@PGF/GM hydrogels can enhance the chondrogenesis of BMSCs and promote neocartilage formation in the rabbit cartilage defect model.

Regulation of Osteoimmune Microenvironment and Osteogenesis by 3D-Printed PLAG/black Phosphorus Scaffolds for Bone Regeneration.

The treatment of bone defects remains a significant challenge to be solved clinically. Immunomodulatory properties of orthopedic biomaterials have significance in regulating osteoimmune microenvironment for osteogenesis. A lactic acid-co-glycolic acid (PLGA) scaffold incorporates black phosphorus (BP) fabricated by 3D printing technology to investigate the effect of BP on osteoimmunomodulation and osteogenesis in site. The PLGA/BP scaffold exhibits suitable biocompatibility, biodegradability, and mechanical properties as an excellent microenvironment to support new bone formation. The studies' result also demonstrate that the PLGA/BP scaffolds are able to recruit and stimulate macrophages M2polarization, inhibit inflammation, and promote human bone marrow mesenchymal stem cells (hBMSCs) proliferation and differentiation, which in turn promotes bone regeneration in the distal femoral defect region of steroid-associated osteonecrosis (SAON) rat model. Moreover, it is screened and demonstrated that PLGA/BP scaffolds can promote osteogenic differentiation by transcriptomic analysis, and PLGA/BP scaffolds promote osteogenic differentiation and mineralization by activating PI3K-AKTsignaling pathway in hBMSC cells. In this study, it is shown that the innovative PLGA/BP scaffolds are extremely effective in stimulating bone regeneration by regulating macrophage M2 polarization and a new strategy for the development of biomaterials that can be used to repair bone defects is offered.

BAG3 regulates bone marrow mesenchymal stem cell proliferation by targeting INTS7.

BAG3 is an essential regulator of cell survival and has been investigated in the context of heart disease and cancer. Our previous study used immunoprecipitation-liquid chromatography-tandem mass spectrometry to show that BAG3 might directly interact with INTS7 and regulate bone marrow mesenchymal stem cell (BMMSCs) proliferation. However, whether BAG3 bound INTS7 directly and how it regulated BMMSCs expansion was unclear. BAG3 expression was detected by quantitative real-time PCR in BMMSCs after siRNA-mediated BAG3 knockdown. BMMSC proliferation was determined using the CCK-8 and colony formation assays. The transwell migration, flow cytometry and TUNEL assays were performed to measure BMMSC migration, cell cycle and apoptosis, respectively. Moreover, co-immunoprecipitation, protein half-life assay and western blotting analyses were used to determine the regulatory mechanism underlying the BAG3-mediated increase in BMMSC proliferation. The results showed that knocking down BAG3 in BMMSCs markedly decreased their proliferative activity, colony formation and migratory capacity, and induced cell apoptosis as well as cell cycle arrest. Meanwhile, overexpression of BAG3 had the opposite effect. Bioinformatics and BAG3-INTS7 co-immunoprecipitation analyses revealed that BAG3 directly interacted with INTS7. Moreover, the downregulation of BAG3 inhibited the expression of INTS7 and promoted its ubiquitination. We also observed that BAG3 knockdown increased the levels of reactive oxygen species and the extent of DNA damage in BMMSCs. Notably, the upregulation of INTS7 or the addition of an antioxidant scavenger could rescue the BMMSC phenotype induced by BAG3 downregulation. BAG3 directly interacts with INTS7 and promotes BMMSC expansion by reducing oxidative stress.

Nacre-mimetic cerium-doped nano-hydroxyapatite/chitosan layered composite scaffolds regulate bone regeneration via OPG/RANKL signaling pathway

Autogenous bone grafting has long been considered the gold standard for treating critical bone defects. However, its use is plagued by numerous drawbacks, such as limited supply, donor site morbidity, and restricted use for giant-sized defects. For this reason, there is an increasing need for effective bone substitutes to treat these defects. Mollusk nacre is a natural structure with outstanding mechanical property due to its notable “brick-and-mortar” architecture. Inspired by the nacre architecture, our team designed and fabricated a nacre-mimetic cerium-doped layered nano-hydroxyapatite/chitosan layered composite scaffold (CeHA/CS). Hydroxyapatite can provide a certain strength to the material like a brick. And as a polymer material, chitosan can slow down the force when the material is impacted, like an adhesive. As seen in natural nacre, the combination of these inorganic and organic components results in remarkable tensile strength and fracture toughness. Cerium ions have been demonstrated exceptional anti-osteoclastogenesis capabilities. Our scaffold featured a distinct layered HA/CS composite structure with intervals ranging from 50 to 200 μm, which provided a conducive environment for human bone marrow mesenchymal stem cell (hBMSC) adhesion and proliferation, allowing for in situ growth of newly formed bone tissue. In vitro, Western-blot and qPCR analyses showed that the CeHA/CS layered composite scaffolds significantly promoted the osteogenic process by upregulating the expressions of osteogenic-related genes such as RUNX2, OCN, and COL1, while inhibiting osteoclast differentiation, as indicated by reduced TRAP-positive osteoclasts and decreased bone resorption. In vivo, calvarial defects in rats demonstrated that the layered CeHA/CS scaffolds significantly accelerated bone regeneration at the defect site, and immunofluorescence indicated a lowered RANKL/OPG ratio. Overall, our results demonstrate that CeHA/CS scaffolds offer a promising platform for bone regeneration in critical defect management, as they promote osteogenesis and inhibit osteoclast activation.

Triple-functional bone adhesive with enhanced internal fixation, bacteriostasis and osteoinductive properties for open fracture repair.

At present, effective fixation and anti-infection implant materials represent the mainstay for the treatment of open fractures. However, external fixation can cause nail tract infections and is ineffective for fixing small fracture fragments. Moreover, closed reduction and internal fixation during the early stage of injury can lead to potential bone infection, conducive to bone nonunion and delayed healing. Herein, we designed a bone adhesive with anti-infection, osteogenic and bone adhesion fixation properties to promote reduction and fixation of open fractures and subsequent soft tissue repair. It was prepared by the reaction of gelatin (Gel) and oxidized starch (OS) with vancomycin (VAN)-loaded mesoporous bioactive glass nanoparticles (MBGNs) covalently cross-linked with Schiff bases. Characterization and adhesion experiments were conducted to validate the successful preparation of the Gel-OS/VAN@MBGNs (GOVM-gel) adhesive. Meanwhile, in vitro cell experiments demonstrated its good antibacterial effects with the ability to stimulate bone marrow mesenchymal stem cell (BMSCs) proliferation, upregulate the expression of alkaline phosphatase (ALP) and osteogenic proteins (RunX2 and OPN) and enhance the deposition of calcium nodules. Additionally, we established a rat skull fracture model and a subcutaneous infection model. The histological analysis showed that bone adhesive enhanced osteogenesis, and in vivo experiments demonstrated that the number of inflammatory cells and bacteria was significantly reduced. Overall, the adhesive could promote early reduction of fractures and antibacterial and osteogenic effects, providing the foothold for treatment of this patient population.

Fabrication and Characterisation of the Cytotoxic and Antibacterial Properties of Chitosan-Cerium Oxide Porous Scaffolds.

Bone damage arising from fractures or trauma frequently results in infection, impeding the healing process and leading to complications. To overcome this challenge, we engineered highly porous chitosan scaffolds (S1, S2, and S3) by incorporating 30 (wt)% iron-doped dicalcium phosphate dihydrate (Fe-DCPD) minerals and different concentrations of cerium oxide nanoparticles (CeO2) (10 (wt)%, 20 (wt)%, and 30 (wt)%) using the lyophilisation technique. The scaffolds were specifically designed for the controlled release of antibacterial agents and were systematically characterised by utilising Raman spectroscopy, X-ray diffraction, scanning electron microscopy, and energy-dispersive X-ray spectroscopy methodologies. Alterations in the physicochemical properties, encompassing pore size, swelling behaviour, degradation kinetics, and antibacterial characteristics, were observed with the escalating CeO2 concentrations. Scaffold cytotoxicity and its impact on human bone marrow mesenchymal stem cell (BM-MSCs) proliferation were assessed employing the 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assay. The synthesised scaffolds represent a promising approach for addressing complications associated with bone damage by fostering tissue regeneration and mitigating infection risks. All scaffold variants exhibited inhibitory effects on bacterial growth against Staphylococcus aureus and Escherichia coli strains. The scaffolds manifested negligible cytotoxic effects while enhancing antibacterial properties, indicating their potential for reducing infection risks in the context of bone injuries.

Taohong Siwu Decoction enhances human bone marrow mesenchymal stem cells proliferation, migration and osteogenic differentiation via VEGF-FAK signaling in vitro.

Taohong Siwu Decoction (THSWD) is a conventional traditional Chinese prescription aiming at promoting blood circulation and alleviating blood stasis. It is widely prescribed in instances of ischemic strokes, cardiovascular diseases, osteoporosis and bone fracture. However, its molecular functions in bone formation remain uncharacterized. This study aims to explore the potential effects of THSWD treatment on human bone marrow mesenchymal stem cells (BMSCs) proliferation, osteogenic differentiation, and migration. BMSCs undergo osteogenic, adipogenic, and chondrogenic differentiation to determine cell stemness. BMSCs were treated with low dose (200μg/ml), medium dose (400μg/ml) and high dose (600μg/ml) THSWD. The cell viability was determined by CCK-8 assays, the osteogenic differentiation ability was determined by alizarin red staining and ALP staining, and cell migration was determined by wound healing and transwell assays. The effect of THSWD on the vascular endothelial growth factor (VEGF)/focal adhesion kinase (FAK) pathway was determined by immunoblotting. THSWD time-dependently and dose-dependently promoted BMSC viability. Moreover, THSWD also promoted BMSC osteogenic differentiation and migration. As opposed to THSWD, VEGF receptor inhibitor Bevacizumab suppressed BMSC osteogenic differentiation and migration. In BMSCs that have been co-treated with THSWD and Bevacizumab, THSWD effects on BMSC functions were partially eliminated by Bevacizumab. Moreover, THSWD treatment boosted VEGF content in the supernatant and was conducive to the phosphorylation of FAK and Src, whereas Bevacizumab exerted opposite effects; similarly, Bevacizumab partially abolished THSWD effects on VEGF and FAK (Tyr397) and Src (Tyr418) phosphorylation. THSWD enhances the capacities of BMSCs to proliferate, differentiate, and migrate, possibly through VEGF and the FAK-Src, thereby improving fracture healing.

Effects of astragaloside IV on glucocorticoid-induced avascular necrosis of the femoral head via regulating Akt-related pathways.

We investigated the role of astragaloside IV (AS-IV) in preventing glucocorticoid-induced avascular necrosis of the femoral head (ANFH) and the underlying molecular mechanisms. Network pharmacology was used to predict the molecular targets of AS-IV. Molecular dynamic simulations were performed to explore the binding mechanism and interaction mode between AS-IV and Akt. Rat models of glucocorticoid-induced ANFH with AS-IV intervention were established, and osteogenesis, angiogenesis, apoptosis and oxidative stress were evaluated before and after blocking the PI3K/Akt pathway with LY294002. The effects of glucocorticoid and AS-IV on bone marrow mesenchymal stem cells and human umbilical vein endothelial cells incubated with and without LY294002 were determined. Downregulated p-Akt expression could be detected in the femoral heads of glucocorticoid-induced ANFH patients and rats. AS-IV increased trabecular bone integrity and vessel density of the femoral head in the model rats. AS-IV increased Akt phosphorylation and upregulated osteogenesis-, angiogenesis-, apoptosis- and oxidative stress-related proteins and mRNA and downregulated Bax, cleaved caspase-3 and cytochrome c levels. AS-IV promoted human umbilical vein endothelial cell migration, proliferation and tube formation ability; bone marrow mesenchymal stem cell proliferation; and osteogenic differentiation under glucocorticoid influence. AS-IV inhibited apoptosis. LY294002 inhibited these effects. AS-IV prevented glucocorticoid-induced ANFH by promoting osteogenesis and angiogenesis via the Akt/Runx2 and Akt/HIF-1α/VEGF pathways, respectively, and suppressing apoptosis and oxidative stress via the Akt/Bad/Bcl-2 and Akt/Nrf2/HO-1 pathways, respectively.

Exosomes from CD133+ human urine-derived stem cells combined adhesive hydrogel facilitate rotator cuff healing by mediating bone marrow mesenchymal stem cells

The inadequate regeneration of natural tissue (mainly fibrocartilage) between tendon and bone during rotator cuff (RC) repair results in an unsatisfactory quality of RC healing. Cell-free therapy based on stem cell exosomes is a safer and more promising approach for tissue regeneration. Here, we investigated the effect of exosomes from human urine-derived stem cells (USCs) and their subpopulations (CD133+USCs) on RC healing. USCs were isolated from urine and sorted by flow cytometry to obtain CD133+ urine-derived stem cells (CD133+ USCs). Urine-derived stem cell exosomes (USC-Exos) and CD133+ urine-derived stem cell exosomes (CD133+ USC-Exos) were subsequently isolated from the cell supernatant and identified by transmission electron microscopy (TEM), particle size analysis, and Western blot. We performed in vitro functional assays to evaluate the effects of USC-Exos and CD133+ USC-Exos on human bone marrow mesenchymal stem cells (BMSCs) proliferation, migration, osteogenic differentiation, and chondrogenic differentiation. In vivo experiments were performed by local injection of exosome-hydrogel complexes for the treatment of RC injury. The effects of CD133+ USC-Exos and USC-Exos on RC healing were assessed from imaging, histological, and biomechanical tests. CD133+ USCs were positive for CD29, CD44, CD73, CD90, CD133, but negative for CD34 and CD45. Differentiation ability test results showed that both USCs and CD133+ USCs had the potential for osteogenic, chondrogenic, and adipogenic differentiation, but CD133+ USCs had stronger chondrogenic differentiation ability. CD133+ USC-Exos and USC-Exos could be efficiently taken up by BMSCs and promote their migration, osteogenic and chondrogenic differentiation. However, CD133+ USC-Exos could promote the chondrogenic differentiation of BMSCs more than USC-Exos. Compared with USC-Exos, CD133+ USC-Exos could promote the healing of bone-tendon interface (BTI) more effectively, which might be related to its ability to promote the differentiation of BMSCs into chondroblasts. Although the two exosomes exhibited the same effect in promoting subchondral bone repair in BTI, the CD133+ USC-Exos group had higher histological scores and stronger biomechanical properties. CD133+ USC-Exos hydrogel complex may become a promising therapeutic approach for RC healing based on stem cell exosomes. This is the first study to assess the specific role of CD133+ USC-Exos in RC healing which may be related to the activation of BMSCs by CD133+ USC-Exos towards chondrogenic differentiation. Further, our study provides a reference for possible future treatment of BTI by applying CD133+ USC-Exos hydrogel complex.

Thermodynamic 2D Silicene for Sequential and Multistage Bone Regeneration.

Bone healing is a multistage process involving the recruitment of cells, revascularization, and osteogenic differentiation, all of which are modulated in the temporal sequence to maximize cascade bone regeneration. However, insufficient osteoblast cells, poor blood supply, and limited bone induction at the site of critical-sized bone defect broadly impede bone repair. 2D SiO2 -silicene@2,2'-,azobis(2-[2-imidazolin-2-yl] propane) (SNSs@AIPH) with inherent thermodynamic property and osteoinductive activity is therefore designed and engineered for sequentially efficient bone repair. By means of controllable NIR-II irradiation, the integrated SNSs@AIPH stimulates the generation of appropriate intracellular reactive oxygen species, which accelerates early bone marrow mesenchymal stem cells (BMSCs) proliferation and angiogenesis remarkably. Importantly, as silicon-based 2D nanoparticles, the engineered SNSs@AIPH with high biocompatibility features distinct bioactivity to significantly promote BMSCs osteogenesis differentiation by activating TGFβ and BMP pathways. In a rat cranial defect model, SNSs@AIPH-NIR-II leads to a comparable increase of BMSCs proliferation and local vascularization at an early stage, followed by significant osteogenic differentiation, synergically resulting in a highly effective bone repair. Collectively, the fascinating characteristics and exceptional bone repair efficiency of NIR-II-mediated SNSs@AIPH allow it to be a promising bionic-oriented strategy for bone regeneration, broadening a new perspective in the application of cell-instructive biomaterials in bone tissue engineering.

The additive effects of bioactive glasses and photobiomodulation on enhancing bone regeneration.

Bioactive glasses (BG) have been generally used in bone defects repair for its good osteoinductivity and osteoconductivity. However, the early angiogenesis of BG in the repair of large-sized bone defects may not be sufficient enough to support new bone formation, resulting in the failure of bone repair. Photobiomodulation (PBM) therapy, which is superior on promoting early angiogenesis, may contribute to the angiogenesis of BG and further enhance the repair of bone defects. Therefore, we applied BG and PBM in combination and preliminarily investigated their additive effects on bone regeneration both in vitro and in vivo. The in vitro results revealed that BG combined with PBM remarkably enhanced human bone marrow mesenchymal stem cells proliferation, osteogenic-related genes expression and mineralization, which was better than applying BG or PBM respectively. For in vivo studies, the histological staining results showed that BG induced new bone formation in the interior of defects and promoted new bone reconstruction at 6 weeks post-operation. The micro-computed tomography results further confirmed that BG combined with PBM accelerated bone formation and maturation, improved the speed and quality of bone regeneration, and promoted bone repair. In conclusion, with the optimum BG and PBM parameters, BG combined with PBM generated additive effects on promoting bone regeneration.

Osteogenic Efficacy of Human Trophoblasts-Derived Conditioned Medium on Mesenchymal Stem Cells.

Trophoblasts play an important role in the regulation of the development and function of the placenta. Our recent study demonstrated the skin regeneration capacity of trophoblast-derived extracellular vesicles (EV). Here, we aimed to determine the potential of trophoblast-derived conditioned medium (TB-CM) in enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We found that TB-CM promoted the osteogenic differentiation of MSCs in a dose-dependent manner. Furthermore, it inhibited adipogenesis of MSCs. We also found that the primary trophoblast-derived conditioned medium (PTB-CM) significantly enhanced the proliferation and osteogenic differentiation of human MSCs. Our study demonstrated the regulatory mechanisms underlying the TB-CM-induced osteogenesis in MSCs. An upregulation of genes associated with cytokines/chemokines was observed. The treatment of MSCs with TB-CM stimulated osteogenesis by activating several biological processes, such as mitogen-activated protein kinase (MAPK) and bone morphogenetic protein 2 (BMP2) signaling. This study demonstrated the proliferative and osteogenic efficacies of the trophoblast-derived secretomes, suggesting their potential for use in clinical interventions for bone regeneration and treatment.

Fabrication and in vitro evaluation of 3D printed porous silicate substituted calcium phosphate scaffolds for bone tissue engineering.

Silicate-substituted calcium phosphate (Si-CaP) ceramics, alternative materials for autogenous bone grafting, exhibit excellent osteoinductivity, osteoconductivity, biocompatibility, and biodegradability; thus, they have been widely used for treating bone defects. However, the limited control over the spatial structure and weak mechanical properties of conventional Si-CaP ceramics hinder their wide application. Here, we used digital light processing (DLP) printing technology to fabricate a novel porous 3D printed Si-CaP scaffold to enhance the scaffold properties. Scanning electron microscopy, compression tests, and computational fluid dynamics simulations of the 3D printed Si-CaP scaffolds revealed a uniform spatial structure, appropriate mechanical properties, and effective interior permeability. Furthermore, compared to Si-CaP groups, 3D printed Si-CaP groups exhibited sustained release of silicon (Si), calcium (Ca), and phosphorus (P) ions. Furthermore, 3D printed Si-CaP groups had more comprehensive and persistent osteogenic effects due to increased osteogenic factor expression and calcium deposition. Our results show that the 3D printed Si-CaP scaffold successfully improved bone marrow mesenchymal stem cells(BMSCs) adhesion, proliferation, and osteogenic differentiation and possessed a distinct apatite mineralization ability. Overall, with the help of DLP printing technology, Si-CaP ceramic materials facilitate the fabrication of ideal bone tissue engineering scaffolds with essential elements, providing a promising approach for bone regeneration.

Teriparatide Promotes Bone Marrow Mesenchymal Stem Cells (BMSCs) Proliferation and Differentiation via Down-Regulating miR-298

This study explored whether teriparatide promotes BMSCs proliferation and differentiation via downregulating miR-298 and provided a basis for bone repair. Based on the microarray analysis after teriparatide treatment, qRT-PCR verified the differentially expressed miRNAs and the osteogenic differentiation was assessed by transfection of miRNA overexpression plasmids and miRNA inhibitors. miRNA array analysis and qRT-PCR verification showed that miR-298 was significantly downregulated during teriparatide-induced BMSCs differentiation. miR-298 overexpression significantly inhibited ALP and OPN expression which was promoted by transfection of miR-298 inhibitor. miR-298 is a negative regulator of BMSCs differentiation induced by teriparatide. Dlx5 is the target of miR-298. Inhibition of DLX5 expression by miR-298 was involved in the osteogenic differentiation of BMSCs. In conclusion, miR-298 negatively regulates the differentiation of BMSCs induced by teriparatide by targeting DLX5, providing a possible therapeutic target for bone tissue repair and regeneration.