The transdifferentiation of human dedifferentiated fat cells into fibroblasts: An in vitro experimental pilot study.

BACKGROUND: Skin grafting is a common method of treating damaged skin; however, surgical complications may arise in patients with poor health. Currently, no effective conservative treatment is available for extensive skin loss. Mature adipocytes, which constitute a substantial portion of adipose tissue, have recently emerged as a potential source of stemness. When de-lipidated, these cells exhibit fibroblast-like characteristics and the ability to redifferentiate, offering homogeneity and research utility as "dedifferentiated fat cells." METHODS AND RESULTS: We conducted an in vitro study to induce fibroblast-like traits in the adipose tissue by transdifferentiating mature adipocytes for skin regeneration. Human subcutaneous fat tissues were isolated and purified from mature adipocytes that underwent a transformation process over 14 days of cultivation. Microscopic analysis revealed lipid degradation over time, ultimately transforming cells into fibroblast-like forms. Flow cytometry was used to verify their characteristics, highlighting markers such as CD90 and CD105 (mesenchymal stem cell markers) and CD56 and CD106 (for detecting fibroblast characteristics). Administering dedifferentiated fat cells with transforming growth factor-ß at the identified optimal differentiation concentration of 5 ng/mL for a span of 14 days led to heightened expression of alpha smooth muscle actin and fibronectin, as evidenced by RNA and protein analysis. Meanwhile, functional validation through cell sorting demonstrated limited fibroblast marker expression in both treated and untreated cells after transdifferentiation by transforming growth factor-ß. CONCLUSION: Although challenges remain in achieving more effective transformation and definitive fibroblast differentiation, our trial could pave the way for a novel skin regeneration treatment strategy.

Pedicled abdominal flap using deep inferior epigastric artery perforators for forearm reconstruction: A case report.

BACKGROUND: Pedicled abdominal flaps are a widely used surgical technique for forearm reconstruction in patients with soft tissue defects. However, some drawbacks include restricted flap size, partial flap loss, and donor-site morbidity. To address these concerns, we present a case of a pedicled abdominal flap using the deep inferior epigastric artery perforators (DIEP) for forearm reconstruction in a patient with a large soft tissue defect. CASE SUMMARY: A 46-year-old male patient was admitted to our hospital with forearm injury caused by a pressing machine. A 15 cm × 10 cm soft tissue defect with complete rupture of the ulnar side structures of the forearm was found. One week after orthopedic management of the neurovascular injury and fractures using the first stage of Masquelet technique, the patient was referred to the plastic and reconstructive surgery department for wound coverage. Surgical debridement and negative-pressure wound therapy revealed a 20 cm × 15 cm soft tissue defect. A pedicle abdominal flap with the DIEP was used to cover the defect. Three weeks later, the flap was detached from the abdomen, and the abdominal defect was directly closed. Subsequently, the second stage of Masquelet technique was performed at the fracture site at week 10. Finally, all donor and recipient sites healed without complications, such as flap dehiscence, infection, hematoma, or necrosis. Fracture site osteosynthesis was achieved without complications. CONCLUSION: Pedicled abdominal flap using the DIEP provides a reliable option for forearm reconstruction in patients with large soft tissue defects.

Nervonic Acid Inhibits Replicative Senescence of Human Wharton's Jelly-Derived Mesenchymal Stem Cells.

Cellular senescence causes cell cycle arrest and promotes permanent cessation of proliferation. Since the senescence of mesenchymal stem cells (MSCs) reduces proliferation and multipotency and increases immunogenicity, aged MSCs are not suitable for cell therapy. Therefore, it is important to inhibit cellular senescence in MSCs. It has recently been reported that metabolites can control aging diseases. Therefore, we aimed to identify novel metabolites that regulate the replicative senescence in MSCs. Using a fecal metabolites library, we identified nervonic acid (NA) as a candidate metabolite for replicative senescence regulation. In replicative senescent MSCs, NA reduced senescence-associated ß-galactosidase positive cells, the expression of senescence-related genes, as well as increased stemness and adipogenesis. Moreover, in non-senescent MSCs, NA treatment delayed senescence caused by sequential subculture and promoted proliferation. We confirmed, for the first time, that NA delayed and inhibited cellular senescence. Considering optimal concentration, duration, and timing of drug treatment, NA is a novel potential metabolite that can be used in the development of technologies that regulate cellular senescence.

Orbital wall restoration with primary bone fragments in complex orbital fractures.

BACKGROUND: Complex orbital fractures are impure orbital fractures because they involve the orbital walls and mid-facial bones. The author reported an orbital wall restoration technique in which the primary orbital wall fragments were restored to their prior position in complex orbital fractures in 2020. As a follow-up to a previous preliminary study, this study retrospectively reviewed the surgical results of complex orbital wall fractures over a 4-year period and compared the surgical outcomes by dividing them into groups with and without balloon restoration. METHODS: Data of 939 patients with facial bone fractures between August 2018 and August 2022 were reviewed. Of these, 154 had complex orbital fractures. Among them, 44 and 110 underwent reduction with and without the balloon technique respectively. Pre- and postoperative Naugle exophthalmometer (Good-Lite Co.) scales were evaluated. The orbital volume and orbital volume ratio were calculated from preoperative and 6 months postoperative computed tomography images. RESULTS: Among 154 patients with complex orbital fractures, 44 patients underwent restoration with the balloon technique, and 110 patients underwent restoration without it. The Naugle scale did not differ significantly between the two groups, but the orbital volume ratio significantly decreased by 3.32% and 2.39% in groups with and without the balloon technique and the difference in OVR was significantly greater in patients in the balloon restoration group compared with the control group. Postoperative balloon rupture occurred in six out of 44 cases (13.64%). None of the six patients with balloon rupture showed significant enophthalmos at 6 months of follow-up. CONCLUSION: The balloon rupture rate was 13.64% (6/44 cases) with marginal screw fixation, blunt screws, and extra protection with a resorbable foam dressing. Furthermore, we restored the orbital wall with primary orbital fragments using balloon support in complex orbital wall fractures.

A retrospective analysis of redo orthognathic surgery: Underlying causes, strategy, and outcome.

The aim of this study was to investigate the underlying causes of the need for redo orthognathic surgery, address surgical strategies, and evaluate postoperative outcomes. A retrospective chart review was conducted involving patients who underwent redo orthognathic surgery between January 2018 and April 2020. A total of 32 patients were included in this study. Prior to the procedures, patients' chief complaints were unfavorable facial profile, asymmetry, relapse, malocclusion, obstructive sleep apnea, and long face. To address these issues, we performed redo orthognathic surgery: this resulted in satisfactory aesthetic and functional outcomes in most cases. Considering the challenging nature of a redo orthognathic surgery, it is crucial for surgeons to accurately evaluate the patient's chief complaints and tailor individualized surgical plans to meet the patient's expectations.

Complications Including Capsular Contracture in Direct-to-Implant Breast Reconstruction With Textured Anatomical Versus Smooth Round Implants: A Single Center Retrospective Analysis.

PURPOSE: Implant-based breast reconstruction is the most common reconstruction method used after mastectomy in breast cancer patients. Many studies have compared the smooth round implants and textured anatomical implants. This study aimed to compare the complications, including capsular contracture, between these two implants used in direct-to-implant (DTI) breast reconstruction. METHODS: This retrospective chart review was performed using a prospectively maintained database from a single center. We identified patients who underwent mastectomy with DTI single-stage breast reconstruction at our hospital between August 2011 and June 2021. The overall complications, including capsular contracture, postoperative infection, seroma, hematoma, implant rupture, implant exposure, rippling, implant malposition, and nipple necrosis, were analyzed. RESULTS: In total, 340 breasts of 323 patients were reconstructed by the DTI approach using either textured anatomical (n = 203) or smooth round (n = 137) implants. The incidence of overall complications and capsular contracture was significantly lower with smooth round implants than with textured anatomical implants. Multivariate analysis showed that smooth round implants were associated with a reduced risk of overall complications (odds ratio [OR], 0.465; 95% confidence interval [CI], 0.265-0.813) and capsular contracture (OR, 0.475; 95% CI, 0.235-0.962). Particularly, smooth round implants were associated with a decreased risk of overall complications in patients not receiving adjuvant chemotherapy and a decreased risk of capsular contracture in patients with body mass index < 25 kg/m² and in those not receiving adjuvant radiotherapy. CONCLUSION: Smooth round implants demonstrated a decreased risk of overall complications and capsular contracture when compared with textured anatomical implants. These results may be utilized in counseling patients regarding the advantages and disadvantages of smooth round implants in DTI breast reconstruction.

Association between Immediate Breast Reconstruction and the Development of Breast Cancer-Related Lymphedema.

BACKGROUND: With the increasing number of patients undergoing immediate breast reconstruction after mastectomy, the impact of immediate breast reconstruction on the risk of breast cancer-related lymphedema has become an emerging area of interest. This study aimed to identify the association between immediate breast reconstruction and postoperative lymphedema. METHODS: A retrospective cohort study was conducted from 2006 to 2016 with 5900 consecutive patients who underwent mastectomy for primary breast cancer with or without immediate breast reconstruction. After excluding patients with synchronous contralateral breast cancer, lymphedema before mastectomy, history of procedures performed in the axillary region, and follow-up data of less than 1 year, the cumulative incidence of lymphedema after immediate breast reconstruction and after no reconstruction was calculated and compared using multivariate Cox regression analysis. RESULTS: Overall, 5497 patients (mean age, 51.7 years) were included, and 630 developed lymphedema. The 5-year cumulative incidence rate of lymphedema was significantly reduced in patients who underwent immediate breast reconstruction versus control patients (9.6% versus 12.2%; P = 0.02). In the multivariate analysis, immediate breast reconstruction status (hazard ratio, 0.75; 95% confidence interval, 0.56 to 0.99; P = 0.042) was an independent predictor for lymphedema. Similar significant associations were observed in the subgroup analyses of patients with a body mass index less than 30 kg/m2 (P = 0.024), in those with fewer than 10 dissected lymph nodes (P = 0.042), or in those with adjuvant radiotherapy (P = 0.048). CONCLUSIONS: Immediate breast reconstruction was associated with a reduced risk of lymphedema. These results may be used for predicting the development of lymphedema following breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Facial injury burden of personal mobility devices: a single-center retrospective analysis.

BACKGROUND: Personal mobility devices (PMDs) have become an increasingly popular transport modality globally. With increasing social interest in and demand for PMDs, the number of individuals visiting emergency departments with PMD-related injuries has also increased annually. This study aimed to evaluate injury patterns and treatment costs for patients treated in the department of plastic surgery in a trauma center. METHODS: In this retrospective study, data concerning patients with PMD-related injuries from January 2017 to December 2021 were reviewed. The data retrieved included age, sex, alcohol consumption, helmet use, the type of impact, onset of injury, place of first visit, type of injury, admission status, operation status, and treatment cost. Multiple linear regression analysis was performed to determine the effects of various factors on cost. RESULTS: Data were collected from 93 patients. Until 2019, the annual number of PMD-related accidents was less than 10; however, this number increased sharply in 2020. The average cost of hospitalization was USD 7,698 whereas the average cost of non-hospitalization was USD 631. Only fractures had a significant association with total cost in linear regression analysis (p < 0.001). CONCLUSION: The prevalence of PMD use and related injuries requiring plastic surgery during the study period showed significant health and financial costs both to the patients involved and to society. This cost could be reduced through stricter regulations concerning PMD use, advocating the use of protective gear, and promoting greater awareness of safety measures and of the consequences of PMD-related accidents.

A New Method of Myostatin Inhibition in Mice via Oral Administration of Lactobacillus casei Expressing Modified Myostatin Protein, BLS-M22.

Myostatin is a member of the transforming growth factor-beta superfamily and is an endogenous negative regulator of muscle growth. This study aimed to determine whether an oral administration of Lactobacillus casei expressing modified human myostatin (BLS-M22) could elicit sufficient levels of myostatin-specific antibody and improve the dystrophic features of an animal model of Duchenne muscular dystrophy (DMD; mdx mouse). BLS-M22 is a recombinant L. casei engineered to harbor the pKV vector and poly-gamma-glutamic acid gene linked to a modified human myostatin gene. Serological analysis showed that anti-myostatin IgG titers were significantly increased, and serum creatine kinase was significantly reduced in the BLS-M22-treated mdx mice compared to the control mice. In addition, treatment of BLS-M22 resulted in a significant increase in body weight and motor function (Rotarod behavior test). Histological analysis showed an improvement in the dystrophic features (fibrosis and muscle hypertrophy) of the mdx mice with the administration of BLS-M22. The circulating antibodies generated after BLS-M22 oral administration successfully lowered serum myostatin concentration. Myostatin blockade resulted in serological, histological, and functional improvements in mdx mice. Overall, the findings suggest the potential of BLS-M22 to treat DMD; however, further clinical trials are essential to ascertain its efficacy and safety in humans.

Midface Infection after COVID-19 Vaccination in a Patient with Calcium Hydroxylapatite Dermal Filler: A Case Report and Literature Review.

The emergence of vaccines for coronavirus disease 2019 (COVID-19) raises risk of possible adverse events from interaction between the vaccines and facial aesthetic care. A 47-year-old female with no medical comorbidities visited our emergency room due to midface painful swelling after 3 hours following receiving the second dose of the messenger RNA BNT162b2 COVID-19 vaccine. About 14 years ago, she underwent nonsurgical augmentation on the nasojugal groove with a calcium hydroxylapatite dermal filler. We performed incision and drainage under general anesthesia on the next day. During operation, yellowish pus-like materials bulged out. After an operation, we performed a combination therapy with antibiotics and methylprednisolone. Her symptoms improved day by day after surgery, and then a complete recovery was achieved at 3 weeks after the treatment. In conclusion, providers of aesthetic procedures are to be aware of the potential risks of such vaccines for patients who already had or seek to receive dermal filler injections.

Wharton's Jelly-Derived Mesenchymal Stem Cells with High Aurora Kinase A Expression Show Improved Proliferation, Migration, and Therapeutic Potential.

Mesenchymal stem cells (MSCs) are effective therapeutic agents that contribute to tissue repair and regeneration by secreting various factors. However, donor-dependent variations in MSC proliferation and therapeutic potentials result in variable production yields and clinical outcomes, thereby impeding MSC-based therapies. Hence, selection of MSCs with high proliferation and therapeutic potentials would be important for effective clinical application of MSCs. This study is aimed at identifying the upregulated genes in human Wharton's jelly-derived MSCs (WJ-MSCs) with high proliferation potential using mRNA sequencing. Aurora kinase A (AURKA) and dedicator of cytokinesis 2 (DOCK2) were selected as the upregulated genes, and their effects on proliferation, migration, and colony formation of the WJ-MSCs were verified using small interfering RNA (siRNA) techniques. mRNA expression levels of both the genes were positively correlated with the proliferation capacity of WJ-MSCs. Moreover, AURKA from human WJ-MSCs regulated the antiapoptotic effect of skeletal muscle cells by upregulating the chemokine (C motif) ligand (XCL1); this was further confirmed in the mdx mouse model. Taken together, the results indicated that AURKA and DOCK2 can be used as potential biomarkers for proliferation and migration of human WJ-MSCs. In particular, human WJ-MSCs with high expression of AURKA might have therapeutic efficacy against muscle diseases, such as Duchenne muscular dystrophy (DMD).

2-IPMA Ameliorates PM2.5-Induced Inflammation by Promoting Primary Ciliogenesis in RPE Cells.

Primary cilia mediate the interactions between cells and external stresses. Thus, dysregulation of primary cilia is implicated in various ciliopathies, e.g., degeneration of the retina caused by dysregulation of the photoreceptor primary cilium. Particulate matter (PM) can cause epithelium injury and endothelial dysfunction by increasing oxidative stress and inflammatory responses. Previously, we showed that PM disrupts the formation of primary cilia in retinal pigment epithelium (RPE) cells. In the present study, we identified 2-isopropylmalic acid (2-IPMA) as a novel inducer of primary ciliogenesis from a metabolite library screening. Both ciliated cells and primary cilium length were increased in 2-IPMA-treated RPE cells. Notably, 2-IPMA strongly promoted primary ciliogenesis and restored PM2.5-induced dysgenesis of primary cilia in RPE cells. Both excessive reactive oxygen species (ROS) generation and activation of a stress kinase, JNK, by PM2.5 were reduced by 2-IPMA. Moreover, 2-IPMA inhibited proinflammatory cytokine production, i.e., IL-6 and TNF-α, induced by PM2.5 in RPE cells. Taken together, our data suggest that 2-IPMA ameliorates PM2.5-induced inflammation by promoting primary ciliogenesis in RPE cells.

Wharton's Jelly-Derived Mesenchymal Stem Cells Reduce Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy by Upregulating microRNA 499.

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3-5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFßR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic "off-the-shelf" cellular products for the treatment of DMD and possibly other muscle disorders.

Triamterene induces autophagic degradation of lysosome by exacerbating lysosomal integrity.

The maintenance of lysosomal integrity is essential for lysosome function and cell fate. Damaged lysosomes are degraded by lysosomal autophagy, lysophagy. The mechanism underlying lysophagy remains largely unknown; this study aimed to contribute to the understanding of this topic. A cell-based screening system was used to identify novel lysophagy modulators. Triamterene (6-phenylpteridine-2,4,7-triamine) was identified as one of the most potent lysophagy inducers from the screening process. We found that triamterene causes lysosomal rupture without affecting other cellular organelles and increases autophagy flux in HepG2 cells. Damaged lysosomes in triamterene-treated cells were removed by autophagy-mediated pathway, which was inhibited by depletion of the autophagy regulator, ATG5 or SQSTM1. In addition, treatment of triamterene decreased the integrity of lysosome and cell viability, which were rescued by removing the triamterene treatment in HepG2 cells. Hence, our data suggest that triamterene is a novel lysophagy inducer through the disruption of lysosomal integrity.

Exposure of Mesenchymal Stem Cells to an Alzheimer's Disease Environment Enhances Therapeutic Effects.

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of Alzheimer's disease (AD). Previous studies suggested that the coculture of human MSCs with AD in an in vitro model reduced the expression of amyloid-beta 42 (Aß42) in the medium as well as the overexpression of amyloid-beta- (Aß-) degrading enzymes such as neprilysin (NEP). We focused on the role of primed MSCs (human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exposed to an AD cell line via a coculture system) in reducing the levels of Aß and inhibiting cell death. We demonstrated that mouse groups treated with naïve MSCs and primed MSCs showed significant reductions in cell death, ubiquitin conjugate levels, and Aß levels, but the effects were greater in primed MSCs. Also, mRNA sequencing data analysis indicated that high levels of TGF-ß induced primed-MSCs. Furthermore, treatment with TGF-ß reduced Aß expression in an AD transgenic mouse model. These results highlighted AD environmental preconditioning is a promising strategy to reduce cell death and ubiquitin conjugate levels and maintain the stemness of MSCs. Further, these data suggest that human WJ-MSCs exposed to an AD environment may represent a promising and novel therapy for AD.

Metformin Inhibits Transforming Growth Factor ß-Induced Fibrogenic Response of Human Dermal Fibroblasts and Suppresses Fibrosis in Keloid Spheroids.

ABSTRACT: Accumulation of excessive extracellular matrix (ECM) and aberrant transforming growth factor ß (TGF-ß) signaling pathway function can be potential therapeutic targets for keloid treatment. In this study, we examined the antifibrotic effect of metformin as a suppressor of TGF-ß signaling pathways in human dermal fibroblasts (HDFs) and keloid spheroids. Human dermal fibroblasts were stimulated with TGF-ß (10 ng/mL) and treated with metformin (10 mM). The mRNA and protein expression of ECM components were evaluated by quantitative polymerase chain reaction, western blot, and immunofluorescence assay. In addition, we immunohistochemically examined the expression levels of ECM proteins in keloid spheroids. After addition of metformin (10 mM), collagen types I and III and elastin mRNA levels were significantly decreased in HDFs, and collagen type I protein level was significantly decreased. In addition, the expression levels of collagen types I and III, fibronectin, and elastin were significantly reduced in keloid spheroids after treatment with metformin (100 mM). Collagen types I and III and p-Smad2/3 complex proteins were decreased in metformin-treated keloid spheroids. These findings indicated that metformin inhibits the expression of ECM components in TGF-ß-stimulated HDFs and keloid spheroids. Therefore, we suggest the potential of metformin as an effective agent for the treatment of keloids.

Staged reconstruction of a chronically infected large skull defect using free tissue transfer and a patient-specific polyetheretherketone implant.

Reconstructions of extensive composite scalp and cranial defects are challenging due to high incidence of postoperative infection and reconstruction failure. In such cases, cranial reconstruction and vascularized soft tissue coverage are required. However, optimal reconstruction timing and material for cranioplasty are not yet determined. Herein, we present a large skull defect with a chronically infected wound that was not improved by repeated debridement and antibiotic treatment for 3 months. It was successfully treated with anterolateral thigh (ALT) free flap transfer for wound salvage and delayed cranioplasty with a patient-specific polyetheretherketone implant. To reduce infection risk, we performed the cranioplasty 1 year after the infection had resolved. In the meantime, depression of ALT flap at the skull defect site was observed, and the midline shift to the contralateral side was reported in a brain computed tomography (CT) scan, but no evidence of neurologic deterioration was found. After the surgery, sufficient cerebral expansion without noticeable dead-space was confirmed in a follow-up CT scan, and there was no complication over the 1-year follow-up period.

Pressure Stimuli Improve the Proliferation of Wharton's Jelly-Derived Mesenchymal Stem Cells under Hypoxic Culture Conditions.

Mesenchymal stem cells (MSCs) are safe, and they have good therapeutic efficacy through their paracrine action. However, long-term culture to produce sufficient MSCs for clinical use can result in side-effects, such as an inevitable senescence and the reduction of the therapeutic efficacy of the MSCs. In order to overcome this, the primary culture conditions of the MSCs can be modified to simulate the stem cells' niche environment, resulting in accelerated proliferation, the achievement of the target production yield at earlier passages, and the improvement of the therapeutic efficacy. We exposed Wharton's jelly-derived MSCs (WJ-MSCs) to pressure stimuli during the primary culture step. In order to evaluate the proliferation, stemness, and therapeutic efficacy of WJ-MSCs, image, genetic, and Western blot analyses were carried out. Compared with standard incubation culture conditions, the cell proliferation was significantly improved when the WJ-MSCs were exposed to pressure stimuli. However, the therapeutic efficacy (the promotion of cell proliferation and anti-apoptotic effects) and the stemness of the WJ-MSCs was maintained, regardless of the culture conditions. Exposure to pressure stimuli is a simple and efficient way to improve WJ-MSC proliferation without causing changes in stemness and therapeutic efficacy. In this way, clinical-grade WJ-MSCs can be produced rapidly and used for therapeutic applications.

Anti-Fibrotic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells on Skeletal Muscle Cells, Mediated by Secretion of MMP-1.

Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2-5-month-old mdx mice intravenously injected with 1 × 105 Wharton's jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD.

Cobalt Chloride Enhances the Anti-Inflammatory Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells through the ERK-HIF-1α-MicroRNA-146a-Mediated Signaling Pathway.

Human mesenchymal stem cells (hMSCs), including human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), which have high proliferation capacity and immunomodulatory properties, are considered to be a good candidate for cell-based therapies. hMSCs show enhanced therapeutic effects via paracrine secretion or cell-to-cell contact that modulates inflammatory or immune reactions. Here, treatment with cobalt chloride (CoCl2) was more effective than naïve hUCB-MSCs in suppressing inflammatory responses in a coculture system with phytohemagglutinin- (PHA-) activated human peripheral blood mononuclear cells (hPBMCs). Furthermore, the effect of CoCl2 is exerted by promoting the expression of anti-inflammatory mediators (e.g., PGE2) and inhibiting that of inflammatory cytokines (e.g., TNF-α and IFN-γ). Treatment of hUCB-MSCs with CoCl2 leads to increased expression of microRNA- (miR-) 146a, which was reported to modulate anti-inflammatory responses. Hypoxia-inducible factor- (HIF-) 1α silencing and ERK inhibition abolished CoCl2-induced miR-146a expression, suggesting that ERK and HIF-1α signals are required for CoCl2-induced miR-146a expression in hUCB-MSCs. These data suggest that treatment with CoCl2 enhances the immunosuppressive capacity of hUCB-MSCs through the ERK-HIF-1α-miR-146a-mediated signaling pathway. Furthermore, pretreatment of transplanted MSCs with CoCl2 can suppress lung inflammation more than naïve MSCs can in a mouse model of asthma. These findings suggest that CoCl2 may improve the therapeutic effects of hUCB-MSCs for the treatment of inflammatory diseases.