Mesenchymal stem cells (MSCs) have been officially approved in many countries to treat graft-versus-host disease, autoimmune disorders and those associated with tissue regeneration after hematopoietic stem cell transplantation. Studies in recent years have confirmed that MSC acts mainly through paracrine mechanism, in which extracellular vesicles secreted by MSC (MSC-EV) play a central role. MSC-EV has overwhelming advantages over MSC itself in the setting of adverse effects in clinical application, indicating that MSC-EV might take the place of its parent cells to be a potentially therapeutic tool for "cell-free therapy". The pharmaceutical properties of MSC-EV largely depend upon the practical and optimal techniques including large-scale expansion of MSC, the modification of MSC based on the indications and the in vivo dynamic features of MSC-EV, and the methods for preparing and harvesting large amounts of MSC-EV. The recent progresses on the issues above will be briefly reviewed.
Humans ; Extracellular Vesicles ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Mesenchymal Stem Cell Transplantation/methods* ; Mesenchymal Stem Cells ; Pharmaceutical Preparations

Dental stem cells (DSCs), an important source of mesenchymal stem cells (MSCs), can be easily obtained by minimally invasive procedures and have been used for the treatment of various diseases. Classic paradigm attributed the mechanism of their therapeutic action to direct cell differentiation after targeted migration, while contemporary insights into indirect paracrine effect opened new avenues for the mystery of their actual low engraftment and differentiation ability in vivo. As critical paracrine effectors, DSC-derived extracellular vesicles (DSC-EVs) are being increasingly linked to the positive effects of DSCs by an evolving body of in vivo studies. Carrying bioactive contents and presenting therapeutic potential in certain diseases, DSC-EVs have been introduced as promising treatments. Here, we systematically review the latest in vivo evidence that supports the therapeutic effects of DSC-EVs with mechanistic studies. In addition, current challenges and future directions for the clinical translation of DSC-EVs are also highlighted to call for more attentions to the (I) distinguishing features of DSC-EVs compared with other types of MSC-EVs, (II) heterogeneity among different subtypes of DSC-derived EVs, (III) action modes of DSC-EVs, (IV) standardization for eligible DSC-EVs and (V) safety guarantee for the clinical application of DSC-EVs. The present review would provide valuable insights into the emerging opportunities of DSC-EVs in future clinical applications.
Cell Differentiation ; Extracellular Vesicles/metabolism* ; Mesenchymal Stem Cell Transplantation/methods* ; Mesenchymal Stem Cells/metabolism*

Mesenchymal stem cells (MSCs) secrete various cytokines with angiogenic and neuroprotective effects. This study aimed to assess the effects of human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on diabetes-related intracavernosal pressure (ICP) impairment in rats. hWJ-MSCs were isolated from human umbilical cord Wharton's jelly and transplanted into the corpus cavernosum of streptozotocin (STZ)-induced diabetic rats by unilateral injection. The erectile function was evaluated at 4 weeks, as well as the expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endothelial nitric oxide synthase (eNOS), and insulin-like growth factor 1 (IGF1). STZ-induced diabetic rats showed impaired ICP, which was significantly improved by hWJ-MSC treatment. VEGF, eNOS, IGF1, and bFGF expression levels were higher in hWJ-MSC injection sites than those in control ones in STZ-induced diabetic rats. These results suggest that hWJ-MSC transplantation might improve diabetic erectile dysfunction through increased production of paracrine growth factors, highlighting a novel potential therapeutic option for erectile dysfunction.
Animals ; Cell Differentiation ; Diabetes Mellitus, Experimental/therapy* ; Erectile Dysfunction/therapy* ; Humans ; Male ; Mesenchymal Stem Cell Transplantation/methods* ; Rats ; Umbilical Cord ; Vascular Endothelial Growth Factor A ; Wharton Jelly

The high incidence of chronic liver disease is a serious threat to public health, and the current comprehensive internal medicine treatment is ineffective. Liver transplantation is limited by the shortage of liver source and post-transplant rejection, and thus unmet the clinical needs. More importantly, cell therapy shows great promise for the treatment of chronic liver disease. Over recent years, domestic and foreign scholars have carried out a variety of cell therapy preclinical and clinical trials for critical liver disease, and achieved certain results, providing new methods for the treatment of chronic liver diseases. This review discusses the cell therapy research status and application progress, various existing problems and challenges, and key issues of mesenchymal stem cells in the treatment of chronic liver diseases.
Cell- and Tissue-Based Therapy ; Humans ; Liver Diseases/therapy* ; Liver Transplantation/methods* ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

BACKGROUND: Several patients experience persistent otorrhea after a flawless surgical procedure because of insufficient epithelial healing. Several efforts, such as autologous tissue allograft and xenograft, have been made to halt otorrhea. However, a stable technology to induce temporal epithelial repair is yet to be established. Therefore, this study aims to investigate whether implantation of seeding adipose-derived mesenchymal stem cell (ADMSC) aggregates on extracellular matrix (ECM; herein, ADMSC aggregate-ECM) into damaged skin wound promotes skin regeneration. METHODS: ADMSC aggregate-ECM was prepared using a previously described procedure that isolated ADMSCs from rabbits and applied to the auricle and auditory meatus wound beds of New Zealand white rabbits. Wound healing was assessed by general observation and hematoxylin and eosin (H&E) staining. Secretion of growth factor of the tissue was evaluated by western blotting. Two other groups, namely, ECM and control, were used. Comparisons of three groups were conducted by one-way analysis of variance analysis. RESULTS: ADMSCs adhered tightly to the ECM and quickly formed cell sheets. At 2 weeks, general observation and H&E staining indicated that the wound healing rates in the ADMSC aggregate-ECM (69.02 ± 6.36%) and ECM (59.32 ± 4.10%) groups were higher than that in the control group (43.74 ± 12.15%; P = 0.005, P < 0.001, respectively) in ear auricle excisional wounds. At 7 weeks, The scar elevation index was evidently reduced in the ADMSC aggregate-ECM (2.08 ± 0.87) and ECM (2.31 ± 0.33) groups compared with the control group (4.06 ± 0.45; P < 0.001, P < 0.001, respectively). In addition, the scar elevation index of the ADMSC aggregate-ECM group reached the lowest rate 4 weeks in advance. In auditory meatus excisional wounds, the ADMSC aggregate-ECM group had the largest range of normal skin-like structure at 4 weeks. The ADMSC aggregate-ECM and ECM groups secreted increased amounts of growth factors that contributed to skin regeneration at weeks 1 and 2, respectively. CONCLUSIONS ADMSC aggregate-ECM and ECM are effective repair materials for wound healing, especially ADMSC aggregate-ECM. This approach will provide a meaningful experimental basis for mastoid epithelium repair in subsequent clinical trials.
Adipose Tissue ; cytology ; Animals ; Cell Differentiation ; physiology ; Cell Proliferation ; physiology ; Cells, Cultured ; Ear Auricle ; cytology ; Extracellular Matrix ; chemistry ; Flow Cytometry ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; cytology ; Microscopy, Electron, Scanning ; Osteogenesis ; physiology ; Rabbits ; Real-Time Polymerase Chain Reaction

Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration.
Animals ; Bone Regeneration ; Cell Differentiation ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; cytology ; Osteogenesis ; Tissue Engineering ; methods ; Tissue Scaffolds

ObjectiveCurrently, magnetic resonance imaging (MRI) is the most commonly used imaging modality for observing the growth and development of mesenchymal stem cells (MSCs) after in vivo transplantation to treat osteoarthritis (OA). However, it is a challenge to accurately monitor the treatment effects of MSCs in the zone of calcified cartilage (ZCC) with OA. This is especially true in the physiological and biochemical views that are not accurately detected by MRI contrast agents. In contrast, ultrashort time echo (UTE) MRI has been shown to be sensitive to the presence of the ZCC, creating the potential for more effectively observing the repair of the ZCC in OA by MSCs. A special focus is given to the outlook of the use of UTE MRI to detect repair of the ZCC with OA through MSCs. The limitations of the current techniques for clinical applications and future directions are also discussed.

Data SourcesUsing the combined keywords: "osteoarthritis", "mesenchymal stem cells", "calcified cartilage", and "magnetic resonance imaging", the PubMed/MEDLINE literature search was conducted up to June 1, 2017.

Study SelectionA total of 132 published articles were initially identified citations. Of the 132 articles, 48 articles were selected after further detailed review. This study referred to all the important English literature in full.

ResultsIn contrast, UTE MRI has been shown to be sensitive to the presence of the ZCC, creating the potential for more effectively observing the repair of the ZCC in OA by MSCs.

ConclusionsThe current studies showed that the ZCC could be described in terms of its histomorphology and biochemistry by UTE MRI. We prospected that UTE MRI has been shown the potential for more effectively observing the repair of the ZCC in OA by MSCs in vivo.

Cartilage, Articular ; diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; methods ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; physiology ; Osteoarthritis ; diagnostic imaging ; therapy

Men with diabetic erectile dysfunction (ED) respond poorly to the currently available oral phosphodiesterase-5 inhibitors. Therefore, functional therapies for diabetic ED are needed. Stromal vascular fraction (SVF) and the adenovirus-mediated cartilage oligomeric matrix angiopoietin-1 (Ad-COMP-Ang1) gene are known to play critical roles in penile erection. We previously reported that SVF and Ad-COMP-Ang1 have only a short-term effect in restoring erectile function. Further improvements to ED therapy are needed for long-lasting effects. In the present study, we aimed to test if the combination of SVF and Ad-COMP-Ang1 could extend the erection effect in diabetic ED. We found that the combination therapy showed a long-term effect in restoring erectile function through enhanced penile endothelial and neural cell regeneration. Combination therapy with SVF and Ad-COMP-Ang1 notably restored cavernous endothelial cell numbers, pericyte numbers, endothelial cell-cell junctions, decreased cavernous endothelial cell permeability, and promoted neural regeneration for at least 4 weeks in diabetic mice. In summary, this is an initial description of the long-term effect of combination therapy with SVF and Ad-COMP-Ang1 in restoring erectile function through a dual effect on endothelial and neural cell regeneration. Such combination therapy may have therapeutic potential for the treatment of diabetic ED.
Angiopoietin-1/genetics* ; Animals ; Diabetes Mellitus, Experimental/metabolism* ; Endothelium, Vascular/metabolism* ; Erectile Dysfunction/therapy* ; Genetic Therapy/methods* ; Intercellular Junctions/metabolism* ; Male ; Mesenchymal Stem Cell Transplantation ; Mice ; Penile Erection/physiology* ; Permeability

Objective: To explore the effects of immediate and delayed intracavernous injection of bone marrow mesenchymal stem cells (BM-MSCs) on neurogenic erectile dysfunction (NED) induced by bilateral cavernous nerve injury in Sprague-Dawley (SD) rats. METHODS: BM-MSCs isolated from male SD rats were cultured and identified. Twenty-eight 8-week-old male SD rats were randomly divided into four groups, sham operation, NED model control, BM-MSCs immediate, and BM-MSCs delayed, and NED models were established in the latter three groups by crushing the bilateral cavernous nerves. The rats in the sham operation and model control groups were injected intracavernously with placebo while those in the latter two with BM-MSCs immediately or 2 weeks after modeling. At 12 weeks after operation, the penile function of the rats was assessed according to the penile intracavernous pressure (ICP), mean arterial pressure (MAP), and ICP/MAP ratio obtained from different groups of rats. Then, all the animals were sacrificed and the penile cavernosal tissue collected for histological analysis. RESULTS: At 12 weeks after modeling, both ICP and ICP/MAP were significantly increased in the BM-MSCs immediate and delayed groups as compared with those in the model control (P <0.05), and so were the ratio of smooth muscle to collagen (P <0.05) and the smooth muscle content in the corpus cavernosum (P <0.05), and the number of neurofilament (NF)-positive nerve fibers (P <0.05) and the expression of neuronal nitric oxide synthase (nNOS) in the dorsal nerves of the midshaft penis (P <0.05). CONCLUSIONS Intracavernous injection of BM-MSCs can improve erectile function in rats with bilateral cavernous nerve injury by elevating the smooth muscle-collagen ratio and smooth muscle content in the corpus cavernosum and thus preventing its fibrosis as well as by increasing the number of NF-positive nerve fibers and expression of nNOS in the penile dorsal nerves.
Animals ; Disease Models, Animal ; Erectile Dysfunction ; enzymology ; etiology ; therapy ; Male ; Mesenchymal Stem Cell Transplantation ; methods ; Muscle, Smooth ; Nitric Oxide Synthase Type I ; metabolism ; Penile Erection ; physiology ; Penis ; enzymology ; innervation ; Pudendal Nerve ; Random Allocation ; Rats ; Rats, Sprague-Dawley