Bone Marrow-derived Mesenchymal Stem Cells Research Articles

Anti-Stress and Anti-ROS Effects of MnOx-Functionalized Thermosensitive Nanohydrogel Protect BMSCs for Intervertebral Disc Degeneration Repair.

Stem cell transplantation has been proven to be a promising strategy for intervertebral disc degeneration (IDD) repair. However, replicative senescence of bone marrow-derived mesenchymal stem cells (BMSCs), shear damage during direct injection, mechanical stress, and the reactive oxygen species (ROS)-rich microenvironment in degenerative intervertebral discs (IVDs) cause significant cellular damage and limit the therapeutic efficacy. Here, an injectable manganese oxide (MnOx)-functionalized thermosensitive nanohydrogel was proposed for BMSC transplantation for IDD therapy. The MnOx-functionalized thermosensitive nanohydrogel not only successfully protected BMSCs from shear force and mechanical stress before and after injection but also repaired the harsh high-ROS environment in degenerative IVDs, thus effectively increasing the viability of BMSCs and resident nucleus pulposus cells (NPCs). The MnOx-functionalized thermosensitive nanohydrogel provides mechanical protection for stem cells and helps to remove endogenous ROS, providing a promising stem cell delivery platform for the treatment of IDD. This article is protected by copyright. All rights reserved.

CircCOX6A1 suppresses osteogenic differentiation and aggravates osteoporosis via miR-512-3p/DYRK2 axis.

Osteoporosis (OP), characterized by compromised bone integrity and increased fracture risk, poses a significant health challenge. Circular RNAs (circRNAs) have emerged as crucial regulators in various pathophysiological processes, prompting investigation into their role in osteoporosis. This study aimed to elucidate the involvement of circCOX6A1 in OP progression and understand its underlying molecular mechanisms. The primary objective was to explore the impact of circCOX6A1 on bone marrow-derived mesenchymal stem cells (BMSCs) and its potential interactions with miR-512-3p and DYRK2. GSE161361 microarray analysis was employed to assess circCOX6A1 expression in OP patients. We utilized in vitro and in vivo models, including BMSC cultures, osteogenic differentiation assays, and an OVX-induced mouse model of OP. Molecular techniques such as quantitative RT-PCR, western blotting, and functional assays like alizarin red staining (ARS) were employed to evaluate circCOX6A1 effects on BMSC proliferation, apoptosis, and osteogenic differentiation. The interaction between circCOX6A1, miR-512-3p, and DYRK2 was investigated through dual luciferase reporter assays, RNA immunoprecipitation, and RNA pull-down assays. CircCOX6A1 was found to be upregulated in osteoporosis patients, and its expression inversely correlated with osteogenic differentiation of BMSCs. CircCOX6A1 knockdown enhanced osteogenic differentiation, as evidenced by increased mineralized nodule formation and upregulation of osteogenic markers. In vivo, circCOX6A1 knockdown ameliorated osteoporosis progression in OVX mice. Mechanistically, circCOX6A1 acted as a sponge for miR-512-3p, subsequently regulating DYRK2 expression. This study provides compelling evidence for the role of circCOX6A1 in osteoporosis pathogenesis. CircCOX6A1 negatively regulates BMSC osteogenic differentiation through the miR-512-3p/DYRK2 axis, suggesting its potential as a therapeutic target for mitigating OP progression.

Cadherin-6 is a novel mediator for the migration of mesenchymal stem cells to glioblastoma cells in response to stromal cell-derived factor-1.

Glioblastoma recruits various nontransformed cells from distant tissues. Although bone marrow-derived mesenchymal stem cells (MSCs) have been observed migrating to glioblastoma, the underlying mechanism driving MSC migration toward glioblastoma remains unclear. Tumor vascularity is critical in the context of recurrent glioblastoma and is closely linked to the expression of stromal cell-derived factor-1 (SDF-1). We demonstrated that cadherin-6 mediated MSC migration both toward SDF-1 and toward glioblastoma cells. Cadherin-6 knockdown resulted in the downregulation of MSCs capacity to migrate in response to SDF-1. Furthermore, MSCs with cadherin-6 knockdown exhibited impaired migration in response to conditioned media derived from glioblastoma cell lines (U87 and U373) expressing SDF-1, thus simulating the glioblastoma microenvironment. Moreover, MSCs enhanced the vasculogenic capacity of U87 cells without increasing the proliferation, cancer stem cell characteristics, or migration of U87. These results suggest that the current strategy of utilizing MSCs as carriers for antiglioblastoma drugs requires careful examination. Furthermore, cadherin-6 may represent a novel potential target for controlling the recruitment of MSCs toward glioblastoma.

Autologous bone marrow-derived mesenchymal stem cells and endothelial progenitor cells transplantation showed potential benefits for type 2 diabetes mellitus Filipino patients: a case series

Autologous bone marrow-derived mesenchymal stem cells and endothelial progenitor cells transplantation showed potential benefits for type 2 diabetes mellitus Filipino patients: a case series

Polycaprolactone/β-Tricalcium Phosphate Composite Scaffolds with Advanced Pore Geometries Promote Human Mesenchymal Stromal Cells' Osteogenic Differentiation.

Critical-sized mandibular bone defects, arising from, for example, resections after tumor surgeries, are currently treated with autogenous bone grafts. This treatment is considered very invasive and is associated with limitations such as morbidity and graft resorption. Tissue engineering approaches propose to use 3D scaffolds that combine structural features, biomaterial properties, cells, and biomolecules to create biomimetic constructs. However, mimicking the complex anatomy and composition of the mandible poses a challenge in scaffold design. In our study, we evaluated the dual effect of complex pore geometry and material composition on the osteogenic potential of 3D printed scaffolds. The scaffolds were made of polycaprolactone (PCL) alone (TCP0), or with a high concentration of β-tricalcium phosphate (β-TCP) up to 40% w/w (TCP40), with two complex pore geometries, namely a star- (S) and a diamond-like (D) shape. Scanning electron microscopy and microcomputed tomography images confirmed high fidelity during the printing process. The D-scaffolds displayed higher compressive moduli than the corresponding S-scaffolds. TCP40 scaffolds in simulated body fluid showed deposition of minerals on the surface after 28 days. Subsequently, we assessed the differentiation of seeded bone marrow-derived human mesenchymal stromal cells (hMSCs) over 28 days. The early expression of RUNX2 in the cell nuclei confirmed the commitment toward an osteogenic phenotype. Moreover, alkaline phosphatase (ALP) activity and collagen deposition displayed an increasing trend in the D-scaffolds. Collagen type I was mainly present in the deposited extracellular matrix (ECM), confirming deposition of bone matrix. Finally, Alizarin Red staining showed successful mineralization on all the TCP40 samples, with higher values for the S-shaped scaffolds. Taken together, our study demonstrated that the complex pore architectures of scaffolds comprised TCP40 stimulated osteogenic differentiation and mineralization of hMSCs in vitro. Future research will aim to validate these findings in vivo.

Designer umbilical cord-stem cells induce alveolar wall regeneration in pulmonary disease models

BackgroundResearchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion.ObjectiveTo develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment.MethodsdUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed.ResultsIncreased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin β1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs.ConclusionWe developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.

Strontium/Silicon/Calcium-Releasing Hierarchically Structured 3D-Printed Scaffolds Accelerate Osteochondral Defect Repair.

Articular cartilage defects are a global challenge, causing substantial disability. Repairing large defects is problematic, often exceeding cartilage's self-healing capacity and damaging bone structures. To tackle this problem, a scaffold-mediated therapeutic ion delivery system is developed. These scaffolds are constructed from poly(ε-caprolactone) and strontium (Sr)-doped bioactive nanoglasses (SrBGn), creating a unique hierarchical structure featuring macropores from 3D printing, micropores, and nanotopologies due to SrBGn integration. The SrBGn-embedded scaffolds (SrBGn-µCh) release Sr, silicon (Si), and calcium (Ca) ions, which improve chondrocyte activation, adhesion, proliferation, and maturation-related gene expression. This multiple ion delivery significantly affects metabolic activity and maturation of chondrocytes. Importantly, Sr ions may play a role in chondrocyte regulation through the Notch signaling pathway. Notably, the scaffold's structure and topological cues expedite the recruitment, adhesion, spreading, and proliferation of chondrocytes and bone marrow-derived mesenchymal stem cells. Si and Ca ions accelerate osteogenic differentiation and blood vessel formation, while Sr ions enhance the polarization of M2 macrophages. The findings show that SrBGn-µCh scaffolds accelerate osteochondral defect repair by delivering multiple ions and providing structural/topological cues, ultimately supporting host cell functions and defect healing. This scaffold holds great promise for osteochondral repair applications.

Cytokine Receptor-like Factor 1 (CRLF1) and Its Role in Osteochondral Repair.

Since cytokine receptor-like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow-derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno-associated virus (AAV) or AAV containing CRLF1 was determined by morphological, histological, and micro computer tomography (CT) analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were determined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes using real-time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondrogenic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and cardiotrophin-like Cytokine (CLC) stimulated catabolic events via STAT3 activation. A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Recent Advances of MSCs in Renal IRI: From Injury to Renal Fibrosis

Renal fibrosis is a pathological endpoint of maladaptation after ischemia-reperfusion injury (IRI), and despite many attempts, no good treatment has been achieved so far. At the core of renal fibrosis is the differentiation of various types of cells into myofibroblasts. MSCs were once thought to play a protective role after renal IRI. However, growing evidence suggests that MSCs have a two-sided nature. In spite of their protective role, in maladaptive situations, MSCs start to differentiate towards myofibroblasts, increasing the myofibroblast pool and promoting renal fibrosis. Following renal IRI, it has been observed that Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) and Renal Resident Mesenchymal Stem Cells (RR-MSCs) play important roles. This review presents evidence supporting their involvement, discusses their potential mechanisms of action, and suggests several new targets for future research.

Exosomes loaded a smart bilayer-hydrogel scaffold with ROS-scavenging and macrophage-reprogramming properties for repairing cartilage defect

Enhancing the regeneration of cartilage defects remains challenging owing to limited innate self-healing as well as acute inflammation arising from the overexpression of reactive oxygen species (ROS) in post-traumatic microenvironments. Recently, stem cell-derived exosomes (Exos) have been developed as potential cell-free therapy for cartilage regeneration. Although this approach promotes chondrogenesis, it neglects the emerging inflammatory microenvironment. In this study, a smart bilayer-hydrogel dual-loaded with sodium diclofenac (DC), an anti-inflammatory drug, and Exos from bone marrow-derived mesenchymal stem cells was developed to mitigate initial-stage inflammation and promote late-stage stem-cell recruitment and chondrogenic differentiation. First, the upper-hydrogel composed of phenylboronic-acid-crosslinked polyvinyl alcohol degrades in response to elevated levels of ROS to release DC, which mitigates oxidative stress, thus reprogramming macrophages to the pro-healing state. Subsequently, Exos are slowly released from the lower-hydrogel composed of hyaluronic acid into an optimal microenvironment for the stimulation of chondrogenesis. Both in vitro and in vivo assays confirmed that the dual-loaded bilayer-hydrogel reduced post-traumatic inflammation and enhanced cartilage regeneration by effectively scavenging ROS and reprogramming macrophages. The proposed platform provides multi-staged therapy, which allows for the optimal harnessing of Exos as a therapeutic for cartilage regeneration.

Cell Instructive Behavior of Composite Scaffolds in a Co-Culture of Human Mesenchymal Stem Cells and Peripheral Blood Mononuclear Cells

The in vitro evaluation of 3D scaffolds for bone tissue engineering in mono-cultures is a common practice; however, it does not represent the native complex nature of bone tissue. Co-cultures of osteoblasts and osteoclasts, without the addition of stimulating agents for monitoring cellular cross-talk, remains a challenge. In this study, a growth factor-free co-culture of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and human peripheral blood mononuclear cells (hPBMCs) has been established and used for the evaluation of 3D-printed scaffolds for bone tissue engineering. The scaffolds were produced from PLLA/PCL/PHBV polymeric blends, with two composite materials produced through the addition of 2.5% w/v nanohydroxyapatite (nHA) or strontium-substituted nanohydroxyapatite (Sr-nHA). Cell morphology data showed that hPBMCs remained undifferentiated in co-culture, while no obvious differences were observed in the mono- and co-cultures of hBM-MSCs. A significantly increased alkaline phosphatase (ALP) activity and osteogenic gene expression was observed in co-culture on Sr-nHA-containing scaffolds. Tartrate-resistant acid phosphatase (TRAP) activity and osteoclastogenic gene expression displayed significantly suppressed levels in co-culture on Sr-nHA-containing scaffolds. Interestingly, mono-cultures of hPBMCs on Sr-nHA-containing scaffolds indicated a delay in osteoclasts formation, as evidenced from TRAP activity and gene expression, demonstrating that strontium acts as an osteoclastogenesis inhibitor. This co-culture study presents an effective 3D model to evaluate the regenerative capacity of scaffolds for bone tissue engineering, thus minimizing time-consuming and costly in vivo experiments.

The treatment efficacy of bone tissue engineering strategy for repairing segmental bone defects under diabetic condition.

Diabetes mellitus is a systematic disease which exert detrimental effect on bone tissue. The repair and reconstruction of bone defects in diabetic patients still remain a major clinical challenge. This study aims to investigate the potential of bone tissue engineering approach to improve bone regeneration under diabetic condition. In the present study, decalcified bone matrix (DBM) scaffolds were seeded with allogenic fetal bone marrow-derived mesenchymal stem cells (BMSCs) and cultured in osteogenic induction medium to fabricate BMSC/DBM constructs. Then the BMSC/DBM constructs were implanted in both subcutaneous pouches and large femoral bone defects in diabetic (BMSC/DBM in DM group) and non-diabetic rats (BMSC/DBM in non-DM group), cell-free DBM scaffolds were implanted in diabetic rats to serve as the control group (DBM in DM group). X-ray, micro-CT and histological analyses were carried out to evaluate the bone regenerative potential of BMSC/DBM constructs under diabetic condition. In the rat subcutaneous implantation model, quantitative micro-CT analysis demonstrated that BMSC/DBM in DM group showed impaired bone regeneration activity compared with the BMSC/DBM in non-DM group (bone volume: 46 ± 4.4mm3 vs 58.9 ± 7.15mm3, *p < 0.05). In the rat femoral defect model, X-ray examination demonstrated that bone union was delayed in BMSC/DBM in DM group compared with BMSC/DBM in non-DM group. However, quantitative micro-CT analysis showed that after 6months of implantation, there was no significant difference in bone volume and bone density between the BMSC/DBM in DM group (199 ± 63mm3 and 593 ± 65mg HA/ccm) and the BMSC/DBM in non-DM group (211 ± 39mm3 and 608 ± 53mg HA/ccm). Our data suggested that BMSC/DBM constructs could repair large bone defects in diabetic rats, but with delayed healing process compared with non-diabetic rats. Our study suggest that biomaterial sacffolds seeded with allogenic fetal BMSCs represent a promising strategy to induce and improve bone regeneration under diabetic condition.

Exosomes Secreted by Wharton's Jelly-Derived Mesenchymal Stem Cells Promote the Ability of Cell Proliferation and Migration for Keratinocyte.

Mesenchymal stem cells (MSCs) isolated from Wharton's jelly (WJ-MSCs) and adipose tissue (AD-MSCs) are alternative sources for bone marrow-derived MSCs. Owing to their multiple functions in angiogenesis, immune modulation, proliferation, migration, and nerve regeneration, MSC-derived exosomes can be applied in "cell-free cell therapy". Here, we investigated the functional protein components between the exosomes from WJ-MSCs and AD-MSCs to explain their distinct functions. Proteins of WJ-MSC and AD-MSC exosomes were collected and compared based on iTRAQ gel-free proteomics data. Results: In total, 1695 proteins were detected in exosomes. Of these, 315 were more abundant (>1.25-fold) in AD-MSC exosomes and 362 kept higher levels in WJ-MSC exosomes, including fibrinogen proteins. Pathway enrichment analysis suggested that WJ-MSC exosomes had higher potential for wound healing than AD-MSC exosomes. Therefore, we treated keratinocyte cells with exosomes and the recombinant protein of fibrinogen beta chain (FGB). It turned out that WJ-MSC exosomes better promoted keratinocyte growth and migration than AD-MSC exosomes. In addition, FGB treatment had similar results to WJ-MSC exosomes. The fact that WJ-MSC exosomes promoted keratinocyte growth and migration better than AD-MSC exosomes can be explained by their higher FGB abundance. Exploring the various components of AD-MSC and WJ-MSC exosomes can aid in their different clinical applications.

Mesenchymal stem cells promote ovarian reconstruction in mice

BackgroundStudies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex cryopreservation is a good choice to preserve female fertility before cancer treatment. Following the remission of the disease, the thawed ovarian tissue can be transplanted back and restore fertility of the patient. However, there is a risk to reintroduce cancer cells in the body and leads to the recurrence of cancer. Given the low success rate of current in vitro culture techniques for obtaining mature oocytes from primordial follicles, an artificial ovary with primordial follicles may be a good way to solve this problem.MethodsIn the study, we established an artificial ovary model based on the participation of mesenchymal stem cells (MSCs) to evaluate the effect of MSCs on follicular development and oocyte maturation. P2.5 mouse ovaries were digested into single cell suspensions and mixed with bone marrow derived mesenchymal stem cells (BM-MSCs) at a 1:1 ratio. The reconstituted ovarian model was then generated by using phytohemagglutinin. The phenotype and mechanism studies were explored by follicle counting, immunohistochemistry, immunofluorescence, in vitro maturation (IVM), in vitro fertilization (IVF), real-time quantitative polymerase chain reaction (RT-PCR), and Terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL) assay.ResultsOur study found that the addition of BM-MSCs to the reconstituted ovary can enhance the survival of oocytes and promote the growth and development of follicles. After transplanting the reconstituted ovaries under kidney capsules of the recipient mice, we observed normal folliculogenesis and oocyte maturation. Interestingly, we found that BM-MSCs did not contribute to the formation of follicles in ovarian aggregation, nor did they undergo proliferation during follicle growth. Instead, the cells were found to be located around growing follicles in the reconstituted ovary. When theca cells were labeled with CYP17a1, we found some overlapped staining with green fluorescent protein(GFP)-labeled BM-MSCs. The results suggest that BM-MSCs may participate in directing the differentiation of theca layer in the reconstituted ovary.ConclusionsThe presence of BM-MSCs in the artificial ovary was found to promote the survival of ovarian cells, as well as facilitate follicle formation and development. Since the cells didn’t proliferate in the reconstituted ovary, this discovery suggests a potential new and safe method for the application of MSCs in clinical fertility preservation by enhancing the success rate of cryo-thawed ovarian tissues after transplantation.

Insights into adhesion and osteogenesis of bone marrow stromal cells promoted by surface nanopatterns

The surface property of biomaterials has a profound influence on the adhesion and biofunction of mesenchymal stem cells, which is vital for successful implantation and regeneration. Nanotopological surface is capable of mimicking bone's extracellular matrix (ECM) to regulate cell behavior, the understanding of which however remains elusive. In this study, we decoupled the effect of nanotopological cues from two perspectives: nanostructure and specific surface area. Bone marrow-derived mesenchymal stem cells (BMSCs) displayed stable and organized F-actin fibers, forming intricate myosin networks on the poly (ε-caprolactone) (PCL) substrate decorated with a well-defined nanopattern that was formed by the PCL lamellae. The cell spreading and myosin activation were limited when the specific surface area of the nanopattern was reduced. These findings illustrate that the specific surface area of the nanopatterned surface is a dominant regulator for cell mechanosensing. Our results highlight the potential of optimizing biomaterial interfaces to enhance cell adhesion and functionality for bone regeneration.

[Zinc finger protein-36 deficiency inhibits osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells and preosteoblasts by activating the ERK/MAPK pathway].

To explore the role of zinc finger protein 36(ZFP36) in regulating osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and preosteoblasts. ZFP36 expression was observed in primary mouse BMSCs and mouse preosteoblasts (MC3T3-E1 cells) during induced osteogenic differentiation. Zfp36-deficient cell models were constructed in the two cells using RNA interference technique and the changes in differentiation capacities of the transfected cells into osteoblasts were observed. Transcriptome sequencing was used to investigate the potential mechanisms of ZFP36 for regulating osteoblast differentiation of the two cells. U0126, a ERK/MAPK signal suppressor, was used to verify the regulatory mechanism of Zfp36 in osteogenic differentiation of Zfp36-deficient cells. During the 14-day induction of osteogenic differentiation, both mouse BMSCs and MC3T3-E1 cells exhibited increased expression of ZFP36, and its mRNA expression reached the peak level on Day 7(P < 0.0001). The Zfp36-deficient cell models showed reduced intensity of alkaline phosphatase (ALP) staining and alizarin red staining with significantly lowered expressions of the osteogenic marker genes including Alpl, Sp7, Bglap and Ibsp (P < 0.01). Transcriptome sequencing verified the reduction of bone mineralization-related gene expressions in Zfp36-deficient cells and indicated the involvement of ERK signaling in the potential regulatory mechanism of Zfp36. Immunoblotting showed that pERK protein expression increased significantly in Zfp36-deficient cells compared with the control cells. In Zfp36-deficient MC3T3-E1 cells, inhibition of activated ERK/MAPK signaling with U0126 resulted in obviously enhanced ALP staining and significantly increased expressions of osteoblast differentiation markers Runx2 and Bglap (P < 0.05). ZFP36 is involved in the regulation of osteoblast differentiation of mouse BMSCs and preosteoblasts, and ZFP36 deficiency causes inhibition of osteoblast differentiation of the cells by activating the ERK/MAPK signaling pathway.

Discovery of YS-1 as a cell line of gastric inflammatory cancer-associated fibroblasts.

Inflammatory cancer-associated fibroblasts (iCAFs) was first identified by co-culture of pancreatic stellate cells and tumor organoids. The key feature of iCAFs is IL-6high/αSMAlow. We examine this phenomenon in gastric cancer using two cell lines of gastric fibroblasts (HGF and YS-1). HGF or YS-1 were co-cultured with MKN7 (a gastric adenocarcinoma cell line) in Matrigel. IL-6 protein levels in the culture supernatant were measured by ELISA. The increased production of IL-6 was not observed in any of the combinations. Instead, the supernatant of YS-1 exhibited the higher levels of IL-6. YS-1 showed IL-6high/αSMA (ACTA2)low in real-time PCR, mRNA-seq and immunohistochemistry. In mRNA-seq, iCAFs-associated genes and signaling pathways were up-regulated in YS-1. No transition to myofibroblastic phenotype was observed by monolayer culture, or the exposure to sonic hedgehog (SHH) or TGF-β. YS-1 conditioned medium induced changes of morphology and stem-ness/differentiation in NUGC-3 (a human gastric adenocarcinoma cell line) and UBE6T-15 (a human bone marrow-derived mesenchymal stem cell line). YS-1 is a stable cell line of gastric iCAFs. This discovery will promote further research on iCAFs for many researchers.

Retraction Note: Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4+CCR6+ Th/Treg cell subset imbalance in ankylosing spondylitis

Retraction Note: Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4+CCR6+ Th/Treg cell subset imbalance in ankylosing spondylitis

Cell-based tissue engineered flexor tendon allograft: A canine in vivo study.

This study aimed to compare the clinically established autologous extrasynovial tendon graft to a newly developed tissue-engineered allograft (Eng-allograft) in terms of functional outcomes following flexor tendon reconstruction in a canine model. The second and fifth flexor digitorum profundus (FDP) tendons from 16 dogs were transected and repaired in Zone II. After 6 weeks of cage activity, the repaired tendons were intentionally ruptured, creating a clinically relevant model for reconstruction. The re-ruptured FDP tendons were then reconstructed using either the clinically standard autologous extrasynovial tendon graft or the Eng-allograft, which had been revitalized with autologous bone marrow-derived mesenchymal stem cells (BMSCs) and synovialized using carbodiimide derivatized synovial fluid (cd-SYN). Following 12 weeks of postoperative rehabilitation, the functional outcomes of the surgical digits were evaluated. The Eng-allograft group exhibited improved digital function, including lower digit work of flexion and reduced adhesion status, while maintaining similar tendon gliding resistance compared to the autograft group. However, the failure load of both the distal and proximal host/graft conjunctions in the Eng-allograft group was significantly lower than that of the autograft group with higher graft rupture at the host-graft junction. In conclusion, the decellularized allogenic intrasynovial tendon, when revitalized BMSCs and synovialized with cd-SYN, demonstrates positive effects on digital function improvement and adhesion reduction. However, the healing at both proximal and distal graft/host junctions is far lower than the autograft. Further research is needed to enhance the healing capacity of allograft conjunctions, aiming to achieve a comparable level of healing seen with autografts.

The IL-6 signaling pathway contributes critically to the immunomodulatory mechanism of human decidua-derived mesenchymal stromal cells

Human bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been proposed as a treatment for graft-versus-host disease (GVHD), which is a major complication following allogeneic hematopoietic cell transplantation. However, clinical trials have not yielded good results, and human decidua-derived mesenchymal stromal cells (DSCs) have been proposed as an alternative. In addition, the mechanism by which DSCs exert their immunomodulatory effects is still unknown. We found that knockdown of IL-6 in DSCs reduced the expression of PD-L1 and PD-L2, which are known as classical immune checkpoint inhibitors. Expression of PD-L1 and PD-L2 was restored by adding recombinant IL-6 to the DSCs. When DSCs and IL-6-knockdown DSCs were administered as treatment in a murine GVHD model, the group receiving IL-6-knockdown DSCs had significantly higher mortality and clinical scores compared to the group receiving DSCs. Taken together, these data suggest that the IL-6 signaling pathway is a crucial contributor to the immunosuppressive capacity of DSCs.