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The continuous production of mature blood cell lineages is maintained by hematopoietic stem cells but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Thus, devising therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and patients receiving radiotherapy. Herein, we describe the preparation of an injectable hydrogel formulation based on Arg‐Gly‐Asp‐alginate (RGD‐Alg) and Laponite using a simple mixing method that ensured a slow and sustained release of interleukin‐12 (IL‐12) (RGD‐Alg/Laponite@IL‐12). The local administration of RGD‐Alg/Laponite@IL‐12 increased survival rates and promoted the hematopoietic recovery of mice who had received sublethal‐dose irradiation. Local intra‐bone marrow (intra‐BM) injection of RGD‐Alg/Laponite@IL‐12 hydrogel effectively stimulated IL12 receptor‐phosphoinositide 3‐kinase/protein kinase B (IL‐12R‐PI3K/AKT) signaling axis, which promoted proliferation and hematopoietic growth factors secretion of BM mesenchymal stem/stromal cells. This signaling axis facilitates the repair of the hematopoietic microenvironment and plays a pivotal role in hematopoietic reconstitution. In conclusion, we describe a biomaterial‐sustained release of IL‐12 for the treatment of irradiated hematopoietic injury and provide a new therapeutic strategy for hematopoietic ARS. [ABSTRACT FROM AUTHOR]

Abstract The continuous production of mature blood cell lineages is maintained by hematopoietic stem cells but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Thus, devising therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and patients receiving radiotherapy. Herein, we describe the preparation of an injectable hydrogel formulation based on Arg‐Gly‐Asp‐alginate (RGD‐Alg) and Laponite using a simple mixing method that ensured a slow and sustained release of interleukin‐12 (IL‐12) (RGD‐Alg/Laponite@IL‐12). The local administration of RGD‐Alg/Laponite@IL‐12 increased survival rates and promoted the hematopoietic recovery of mice who had received sublethal‐dose irradiation. Local intra‐bone marrow (intra‐BM) injection of RGD‐Alg/Laponite@IL‐12 hydrogel effectively stimulated IL12 receptor‐phosphoinositide 3‐kinase/protein kinase B (IL‐12R‐PI3K/AKT) signaling axis, which promoted proliferation and hematopoietic growth factors secretion of BM mesenchymal stem/stromal cells. This signaling axis facilitates the repair of the hematopoietic microenvironment and plays a pivotal role in hematopoietic reconstitution. In conclusion, we describe a biomaterial‐sustained release of IL‐12 for the treatment of irradiated hematopoietic injury and provide a new therapeutic strategy for hematopoietic ARS.

Acute ST-elevation myocardial infarction (STEMI) leads to myocardial injury or necrosis, and M1 macrophages play an important role in the inflammatory response. Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are capable of modulating macrophage plasticity, principally due to their immunoregulatory capacity. In the present study, we analyzed the capacity of MSCs to modulate macrophages derived from monocytes from patients with STEMI. We analyzed the circulating levels of cytokines associated with M1 and M2 macrophages in patients with STEMI, and the levels of cytokines associated with M1 macrophages were significantly higher in patients with STEMI than in controls. BM-MSCs facilitate the generation of M1 and M2 macrophages. M1 macrophages cocultured with MSCs did not have decreased M1 marker expression, but these macrophages had an increased expression of markers of the M2 macrophage phenotype (CD14, CD163 and CD206) and IL-10 and IL-1Ra signaling-induced regulatory T cells (Tregs). M2 macrophages from patients with STEMI had an increased expression of M2 phenotypic markers in coculture with BM-MSCs, as well as an increased secretion of anti-inflammatory cytokines and an increased generation of Tregs. The findings in this study indicate that BM-MSCs have the ability to modulate the M1 macrophage response, which could improve cardiac tissue damage in patients with STEMI. [ABSTRACT FROM AUTHOR]

Static Magnetic Field (SMF) is one of the biophysiological stimulants which modulates physiological processes in different cell lines. Mesenchymal stem cells (MSCs) are important biological tools for regenerative medicine. Although it is known that SMFs cause a change in cellular membrane polarization, oxidative product concentrations, gene expression patterns and cell propagation rates, depending on exposure time and intensity, their effects on MSCs have not been properly explained yet. In this study, MSCs derived from human bone marrow were treated with moderate 328 mT SMF by using cylindric Neodymium Iron Boron (Nd2Fe14B) magnets to investigate its influence on orientation, proliferation rates and morphologies. Results showed that the treated cells gained more homogenous orientation than the non-treated cells, however SMF influence did not significantly change proliferation rates. The cells were grown under both chemically osteogenic induction and SMF to observe the osteogenic differentiation and biomineralization. Alkaline phosphatase (ALP) activity decreased significantly in the cells treated with SMF compared to the control groups. Alizarin Red S staining showed that mineralization also decreased in the cells. The results showed that an easily produced moderate SMF can be a useful physical stimulant to control the fate of MSC both in vitro and in vivo.

A differentiation switch of bone marrow mesenchymal stem/stromal cells (BMSCs) from osteoblasts to adipocytes contributes to age‐ and menopause‐associated bone loss and marrow adiposity. Here it is found that osteocytes, the most abundant bone cells, promote adipogenesis and inhibit osteogenesis of BMSCs by secreting neuropeptide Y (NPY), whose expression increases with aging and osteoporosis. Deletion of NPY in osteocytes generates a high bone mass phenotype, and attenuates aging‐ and ovariectomy (OVX)‐induced bone‐fat imbalance in mice. Osteocyte NPY production is under the control of autonomic nervous system (ANS) and osteocyte NPY deletion blocks the ANS‐induced regulation of BMSC fate and bone‐fat balance. γ‐Oryzanol, a clinically used ANS regulator, significantly increases bone formation and reverses aging‐ and OVX‐induced osteocyte NPY overproduction and marrow adiposity in control mice, but not in mice lacking osteocyte NPY. The study suggests a new mode of neuronal control of bone metabolism through the ANS‐induced regulation of osteocyte NPY. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. BMSCs-derived exosomes (BMSCs-Exo) possess similar functions to their parent cells. In this study, we investigated the therapeutic potential and underlying molecular mechanism for BMSCs-Exo in the treatment of silica-induced pulmonary fibrosis. The rat model of experimental silicosis pulmonary fibrosis was induced with 1.0 mL of one-off infusing silica suspension using the non-exposed intratracheal instillation (50 mg/mL/rat). In vivo transplantation of BMSCs-Exo effectively alleviated silica-induced pulmonary fibrosis, including a reduction in collagen accumulation, inhibition of TGF-β1, and decreased HYP content. Treatment of BMSCs-Exo increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including α-Smooth muscle actin (α-SMA) after exposure to silica suspension. Furthermore, we found that BMSCs-Exo inhibited the expression of Wnt/β-catenin pathway components (P-GSK3β, β-catenin, Cyclin D1) in pulmonary fibrosis tissue. BMSCs-Exo is involved in the alleviation of silica-induced pulmonary fibrosis by reducing the level of profibrotic factor TGF-β1 and inhibiting the progression of epithelial-mesenchymal transition (EMT). Additionally, attenuation of the Wnt/β-catenin signaling pathway closely related to EMT may be one of the mechanisms involved in anti-fibrotic effects of exosomes. [ABSTRACT FROM AUTHOR]

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Cartilage defects resultant from trauma or degenerative diseases (e.g., osteoarthritis) can potentially be repaired using tissue engineering (TE) strategies combining progenitor cells, biomaterial scaffolds and bio-physical/chemical cues. This work examines promoting chondrogenic differentiation of human bone marrow mesenchymal stem/stromal cells (BM-MSCs) by combining the effects of modified poly (ε-caprolactone) (PCL) scaffolds hydrophilicity and chondroitin sulfate (CS) supplementation in a hypoxic 5% oxygen atmosphere. 3D-extruded PCL scaffolds, characterized by μCT, featured a 21 mm−1 surface area to volume ratio, 390 μm pore size and approximately 100% pore interconnectivity. Scaffold immersion in sodium hydroxide solutions for different periods of time had major effects in scaffold surface morphology, wettability and mechanical properties, but without improvements on cell adhesion. In-situ chondrogenic differentiation of BM-MSC seeded in 3D-extruded PCL scaffolds resulted in higher cell populations and ECM deposition along all scaffold structure, when chondrogenesis was preceded by an expansion phase. Additionally, CS supplementation during BM-MSC expansion was crucial to enhance aggrecan gene expression, known as a hallmark of chondrogenesis. Overall, this study presents an approach to tailor the wettability and mechanical properties of PCL scaffolds and supports the use of CS-supplementation as a biochemical cue in integrated TE strategies for cartilage regeneration. [ABSTRACT FROM AUTHOR]

Identification of cues originating from skeletal muscle that govern bone formation is essential for understanding the crosstalk between muscle and bone and for developing therapies for degenerative bone diseases. Here, we identified that skeletal muscle secreted multiple extracellular vesicles (Mu-EVs). These Mu-EVs traveled through the bloodstream to reach bone, where they were phagocytized by bone marrow mesenchymal stem/stromal cells (BMSCs). Mu-EVs promoted osteogenic differentiation of BMSCs and protected against disuse osteoporosis in mice. The quantity and bioactivity of Mu-EVs were tightly correlated with the function of skeletal muscle. Proteomic analysis revealed numerous proteins in Mu-EVs, some potentially regulating bone metabolism, especially glycolysis. Subsequent investigations indicated that Mu-EVs promoted the glycolysis of BMSCs by delivering lactate dehydrogenase A into these cells. In summary, these findings reveal that Mu-EVs play a vital role in BMSC metabolism regulation and bone formation stimulation, offering a promising approach for treating disuse osteoporosis. [Display omitted] • Skeletal muscle secretes Mu-EVs, which can travel via blood vessels to bone • Supplementation with Mu-EVs alleviates disuse osteoporosis after muscle atrophy • Mu-EVs promote osteogenic differentiation of BMSCs by enhancing glycolysis • Glycolic profiles transported by Mu-EVs function as non-canonical myokines In their study, Ma et al. demonstrate that skeletal muscle secretes abundant extracellular vesicles (Mu-EVs). These Mu-EVs promote glycolysis in BMSCs by delivering glycolic profiles to enhance bone formation. The quantity and bioactivity of Mu-EVs are found to correlate with skeletal muscle function. Importantly, supplementation with Mu-EVs is shown to alleviate disuse osteoporosis following muscle atrophy, suggesting a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Abstract: Although exogenous glucocorticoids (GC) play a role in the regulation of bone marrow mesenchymal stem/stromal cells (MSCs) proliferation and differentiation, the function of endogenous GC is not well understood. The purpose of this study was to investigate the effect of the blockage of endogenous GC using RU486, an antagonist of the glucocorticoid receptor, on the in vitro proliferation and differentiation capabilities of human MSCs. We quantitatively measured cell proliferation of human MSCs after treatment with increasing concentrations of RU486. We also evaluated multiple MSC differentiation capabilities, as well as the expression of stemness and senescence genes after proliferation of these human cells in vitro in the presence of RU486 at 10−8 M. It was observed that RU486 treatment significantly increases the proliferation of human MSCs, although the optimal dose of RU486 for this increase in proliferation differs depending on the gender of the MSC donor. This improvement in MSC proliferation with RU486 treatment was higher in MSCs from male donors than that from females. No effect of RU486 on MSC proliferation was observed in a steroid-free medium. RU486 pretreatment significantly increased the expression of mRNA for alkaline phosphatase in human MSCs and the mRNA expression of osteocalcin of these cells up-regulated earlier after their exposure to osteogenic differentiation medium. Although no statistical significance in terms of chondrogenic differentiation markers was detected, mRNA expression for aggrecan and collagen type 2 were higher in a majority of the RU486-pretreated donor MSCs than their untreated controls. No significant difference in terms of MSC adipogenic differentiation capabilities were observed after RU486 treatment. RU486 treatment up-regulated the expressions of FGF-2 and Sox-11 in human MSCs. These results indicate that blockage of endogenous GCs may be developed as a novel approach to effectively improve the proliferation and osteochondral differentiation capabilities of human MSCs for potential clinical applications. Additional studies will be required to determine the potential long-term effects of RU486 treatment on these bone marrow cells. [Copyright &y& Elsevier]