Mesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases. 

/pdf/the-secretion-profile-of-mesenchymal-stem-cells-and-24gtwg4m.pdf

The secretion profile of mesenchymal stem cells and potential applications in treating human diseases

Polydopamine and related polycatecholamines can be easily deposited onto almost any surface from mild, aqueous solution. This results in durable, nanoscale coatings that exhibit high biocompatibility and have useful chemical and electronic properties. Additionally, these materials can be readily chemically and physically modified, and consequently, they are used extensively for surface modification. This review investigates the formation and modification of polycatecholamines; how they adhere to surfaces; and the chemical, physical, and electronic properties of the resultant materials. There is also an exploration of the extraordinary array of applications in which these fascinating materials are employed.

Versatile Surface Modification Using Polydopamine and Related Polycatecholamines: Chemistry, Structure, and Applications

Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn’s disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.

/pdf/mesenchymal-stem-stromal-cells-as-a-valuable-source-for-the-1utdxm1q7g.pdf

Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders.

Engineering a proper immune response following biomaterial implantation is essential to bone tissue regeneration. Herein, a biomimetically hierarchical scaffold composed of deferoxamine@poly(ε‐caprolactone) nanoparticles (DFO@PCL NPs), manganese carbonyl (MnCO) nanosheets, gelatin methacryloyl hydrogel, and a polylactide/hydroxyapatite (HA) matrix is fabricated to augment bone repair by facilitating the balance of the immune system and bone metabolism. First, a 3D printed stiff scaffold with a well‐organized gradient structure mimics the cortical and cancellous bone tissues; meanwhile, an inside infusion of a soft hydrogel further endows the scaffold with characteristics of the extracellular matrix. A Fenton‐like reaction between MnCO and endogenous hydrogen peroxide generated at the implant‐tissue site triggers continuous release of carbon monoxide and Mn2+, thus significantly lessening inflammatory response by upregulating the M2 phenotype of macrophages, which also secretes vascular endothelial growth factor to induce vascular formation. Through activating the hypoxia‐inducible factor‐1α pathway, Mn2+ and DFO@PCL NP further promote angiogenesis. Moreover, DFO inhibits osteoclast differentiation and synergistically collaborates with the osteoinductive activity of HA. Based on amounts of data in vitro and in vivo, strong immunomodulatory, intensive angiogenic, weak osteoclastogenic, and superior osteogenic abilities of such an osteoimmunity‐regulating scaffold present a profound effect on improving bone regeneration, which puts forward a worthy base and positive enlightenment for large‐scale bone defect repair.

Osteoimmunity‐Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration

Bone metabolic disorders include osteolysis, osteoporosis, osteoarthritis and rheumatoid arthritis. Osteoblasts and osteoclasts are two major types of cells in bone constituting homeostasis. The imbalance between bone formation by osteoblasts and bone resorption by osteoclasts has been shown to have a direct contribution to the onset of these diseases. Recent evidence indicates that autophagy and mitophagy, the selective autophagy of mitochondria, may play a vital role in regulating the proliferation, differentiation and function of osteoblasts and osteoclasts. Several signaling pathways, including PINK1/Parkin, SIRT1, MAPK8/FOXO3, Beclin-1/BECN1, p62/SQSTM1, and mTOR pathways, have been implied in the regulation of autophagy and mitophagy in these cells. Here we review the current progress about the regulation of autophagy and mitophagy in osteoblasts and osteoclasts in these bone metabolic disorders, as well as the molecular signaling activated or deactivated during this process. Together, we hope to draw attention to the role of autophagy and mitophagy in bone metabolic disorders, and their potential as a new target for the treatment of bone metabolic diseases and the requirements of further mechanism studies.

/pdf/the-role-of-autophagy-and-mitophagy-in-bone-metabolic-3jx4qzu9om.pdf

The Role of Autophagy and Mitophagy in Bone Metabolic Disorders.

Conditioned medium of human bone marrow-derived stem cells promotes tendon-bone healing of the rotator cuff in a rat model.

Background:Intra-articular steroid injection is a common intervention for frozen shoulder (FS).Purpose:This review aimed to illustrate the effects of intra-articular steroid injection for FS.Study Design:Systematic review and meta-analysis.Methods:PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing intra-articular steroid injection with no injection or sham injections for FS. Visual analog scale (VAS) pain scores were the primary outcome measure. Secondary outcome measures included passive external rotation, abduction, flexion, internal rotation, and functional scores. Complication rates were the safety outcome measure. Comparisons were performed with mean differences (MDs) and 95% confidence intervals (95% CIs). Three time intervals were analyzed: 4 to 6 weeks, 12 to 16 weeks, and 24 to 26 weeks postintervention. Trial sequential analysis was used to verify the pooled results. Line charts were drawn to view the recovery trend in both the intervention a...

Intra-articular Steroid Injection for Frozen Shoulder: A Systematic Review and Meta-analysis of Randomized Controlled Trials With Trial Sequential Analysis:

Skeletal muscle contusion is among the most common injuries in traumatology and clinics of sports medicine. The injured muscle is vulnerable to re-injury owing to fibrosis formation. Given that the bone marrow stromal cell-derived exosomes (BMSC-Exos) displayed promising therapeutic effect for various tissues, we used BMSC-Exos to treat skeletal muscle contusion and investigated its effects on muscle healing. In this study, the in vivo model of skeletal muscle contusion was established by subjecting the tibialis anterior of young male mice to hit injury, and the in vitro inflammation model was established by lipopolysaccharide treatment on macrophages. Macrophage depletion model was built by intraperitoneal injection with clodronate-containing liposomes. Exosomes were isolated and purified from the supernatant of BMSCs using gradient centrifugation. Nanoparticle tracking analysis, transmission electron microscope, and western blot were used to identify the exosomes. HE stain, Masson stain, immunofluorescence, and biomechanical testing were carried out on the muscle tissue. In addition, enzyme-linked immunosorbent assay (ELISA) assays, real-time qPCR, flow cytometry, and PKH67 fluorescence trace were conducted in vitro. Intramuscular injection of BMSC-Exos to mice after muscle contusion alleviated inflammation level, reduced fibrosis size, promoted muscle regeneration, and improved biomechanical property. After macrophages depletion, the effects of BMSC-Exos were inhibited. In vitro, PKH-67 fluorescence was internalized into macrophages. BMSC-Exos promoted M2 macrophages polarization both in vivo and in vitro. At the same time, BMSC-Exos reduced the production of inflammatory cytokines under the inflammatory microenvironment and upregulated anti-inflammatory factors expression. In conclusion, BMSC-Exos attenuated muscle contusion injury and promoted muscle healing in mice by modifying the polarization status of macrophages and suppressing the inflammatory reaction.

Bone Marrow Stromal Cell-Derived Exosomes Promote Muscle Healing Following Contusion Through Macrophage Polarization

https://doi.org/10.1016/j.bioactmat.2022.01.016

Human bone marrow mesenchymal stem cell-derived extracellular vesicles inhibit shoulder stiffness via let-7a/Tgfbr1 axis

Steroid Injection Versus Physiotherapy for Patients With Adhesive Capsulitis of the Shoulder: A PRIMSA Systematic Review and Meta-Analysis of Randomized Controlled Trials

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