Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.

• Bone marrow
• Mesenchymal stem cells
• Liver fibrosis
• In vivo
• Efficiency

• Animals
• Bone Marrow
• Bone Marrow Cells
• Disease Models, Animal
• Humans
• Liver Cirrhosis/therapy
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells

• Cirrhosis
• Exosomes
• Extracellular vesicles
• Macrophages
• Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.

• fibrotic disease
• inflammatory disease
• mesenchymal stem cells (MSCs)
• paracrine factors

• Adipocytes/cytology
• Animals
• Cell Differentiation
• Chondrocytes/cytology
• Fibrosis/therapy
• Humans
• Inflammation/therapy
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Osteoblasts/cytology
• Regenerative Medicine/methods

Liver disease is a major health problem that endangers human health worldwide. Currently, whole organ allograft transplantation is the gold standard for the treatment of end-stage liver disease. A shortage of suitable organs, high costs and surgical complications limit the application of liver transplantation. Mesenchymal stem cell therapy has been considered as a promising alternative approach for end-stage liver disease. Some clinical trials have confirmed the effectiveness of MSC therapy for liver disease, but its application has not been promoted and approved. There are still many issues that should be solved prior to using MSC therapy in clinical applications. The types of liver disease that are most suitable for MSC application should be determined, and the preparation and engraftment of MSCs should be standardized. These may be bottlenecks that limit the use of MSCs. We investigated 22 completed and several ongoing clinical trials to discuss these questions from a clinical perspective. We also discussed the important mechanisms by which MSCs play a therapeutic role in liver disease. Finally, we also proposed novel prospective approaches that can improve the therapeutic effect of MSCs.

• Cell therapy
• Liver disease
• Mesenchymal stem cells

Stem cell therapy is becoming an emerging therapeutic option for chronic liver disease (CLD). However, whether stem cell therapy is more effective than conventional treatment remains questionable. We performed a large-scale meta-analysis of randomized controlled trials (RCTs) to evaluate the therapeutic effects and safety of stem cell therapy for CLD.

We systematically searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases for the period from inception through March 16, 2020. Primary outcomes were all-cause mortality and adverse events related to stem cell therapy. Secondary outcomes included the model for end-stage liver disease score, total bilirubin, albumin, alanine aminotransferase, prothrombin activity, and international normalized ratio. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a random-effects model.

Twenty-four RCTs were included and the majority of these studies showed a high risk of bias. The meta-analysis indicated that compared with conventional treatment, stem cell therapy was associated with improved survival and liver function including the model of end-stage liver disease score, total bilirubin, and albumin levels. However, it had no obvious beneficial effects on alanine aminotransferase level, prothrombin activity, and international normalized ratio. Subgroup analyses showed stem cell therapy conferred a short-term survival benefit for patients with acute-on-chronic liver failure (ACLF), a single injection was more effective than multiple injections, hepatic arterial infusion was more effective than intravenous infusion, and bone marrow-derived stem cells were more effective than those derived from the umbilical cord. Thirteen trials reported adverse events related to stem cell therapy, but no serious adverse events were reported.

Stem cell therapy is a safe and effective therapeutic option for CLD, while patients with ACLF benefit the most in terms of improved short-term survival. A single injection administration of bone marrow-derived stem cells via the hepatic artery has superior therapeutic effects.

• Acute-on-chronic liver failure
• Cell transplantation
• Liver disease
• Stem cell therapy

The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to cause severe acute respiratory symptoms. The occurrence of a cytokine storm in the lungs is a critical step in the disease pathogenesis, as it causes pathological lesions, pulmonary edema, and acute respiratory distress syndrome, potentially resulting in death. Currently, there is no effective treatment that targets the cytokine storm and helps regenerate the damaged tissue. Mesenchymal stem cells (MSCs) are known to act as anti-inflammatory/immunomodulatory candidates and activate endogenous regeneration. As a result, MSC therapy is a potential treatment approach for COVID-19. Intravenous injection of clinical-grade MSCs into COVID-19 patients can induce an immunomodulatory response along with improved lung function. Dental pulp stem cells (DPSCs) are considered a potential source of MSCs for immunomodulation, tissue regeneration, and clinical application. Although some current clinical trials have treated COVID-19 patients with DPSCs, this therapy has not been approved. Here, we review the potential use of DPSCs and their significance in the development of a therapy for COVID-19.

• COVID-19
• coronavirus
• cytokines storm
• dental pulp stem cells
• immunomodulation
• regeneration

• Betacoronavirus/immunology
• COVID-19
• Clinical Trials as Topic
• Coronavirus Infections/immunology
• Coronavirus Infections/therapy
• Cytokines/immunology
• Dental Pulp/cytology
• Dental Pulp/immunology
• Humans
• Immunomodulation
• Immunotherapy/methods
• Inflammation/immunology
• Inflammation/therapy
• Lung/immunology
• Lung/physiology
• Lung Injury/immunology
• Lung Injury/therapy
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/immunology
• Pandemics
• Pneumonia, Viral/immunology
• Pneumonia, Viral/therapy
• Regeneration
• SARS-CoV-2

Leishmaniasis is a neglected disease caused by Leishmania spp. One of its characteristics is an imbalance of host immune responses to foster parasite survival. In this setting, mesenchymal stromal cells (MSCs) may be a viable therapeutic alternative, given their well-established immunomodulatory potential. In this study, we compared the effects of therapy with bone marrow (BM)- and adipose tissue (AD)-derived MSCs in leishmaniasis caused by Leishmania amazonensis in C57BL/6 mice. After determining the most effective MSC source, we then combined these cells with meglumine antimoniate (a pentavalent antimonial commonly used for the treatment of leishmaniasis) to treat the infected mice.

In vitro, co-culture of AD-MSCs and BM-MSCs with Leishmania amazonensis-infected macrophages was performed to understand the influence of both MSC sources in infected cells. In vivo, infected C57BL/6 mice were treated with phosphate-buffered saline (PBS), AD-MSCs and BM-MSCs, and then meglumine antimoniate was combined with MSCs from the most effective source.

In vitro, co-culture of Leishmania amazonensis-infected macrophages with BM-MSCs, compared to AD-MSCs, led to a higher parasite load and lower production of nitric oxide. Fibroblasts grown in conditioned medium from co-cultures with AD-MSCs promoted faster wound healing. Despite a non-significant difference in the production of vascular endothelial growth factor, we observed higher production of tumor necrosis factor-α and interleukin (IL)-10 in the co-culture with AD-MSCs. In vivo, treatment of infected mice with BM-MSCs did not lead to disease control; however, the use of AD-MSCs was associated with partial control of lesion development, without significant differences in the parasite load. AD-MSCs combined with meglumine antimoniate reduced lesion size and parasite load when compared to PBS and AD-MSC groups. At the infection site, we detected a small production of IL-10, but we were unable to detect production of either IL-4 or interferon-γ, indicating resolution of infection without effect on the percentage of regulatory T cells.

Combination treatment of cutaneous leishmaniasis with AD-MSCs and meglumine antimoniate may be a viable alternative.

• Adipose tissue-derived mesenchymal stromal cells
• Bone marrow-derived mesenchymal stromal cells
• Leishmaniasis
• Meglumine antimoniate
• Mesenchymal stromal cells
• Parasite load

Liver disease is a major health issue which present poor clinical treatment performance. Cirrhosis and liver failure are common clinical manifestations of liver diseases. Liver transplantation is recognized as the ultimate and most efficient therapy to the end stage of liver disease. But it was limited by the shortage of honor organs and high cost. Nowadays, stem cell therapy gained more and more attention due to its attractive efficacy in treating liver disease especially in cirrhosis during the clinical trials. Mesenchymal stem cell (MSC) can be differentiated into hepatocytes, promote liver regeneration, inhibit liver fibrosis and induce liver apoptosis, particularly via paracrine mechanisms. This review will highlight recent clinical applications of MSC, providing the available evidence and discussing some unsolved questions in treating liver disease.

• Mesenchymal stem cells (MSCs)
• cirrhosis
• liver disease

Autologous bone marrow stem cell (ABMSC) transplantation has been considered a promising option for hepatitis B virus-related cirrhosis (HBV-C). Although an analysis of the published literature has been performed, the exact effects and safety have yet to be systematically investigated.

We conducted a wide-ranging online search of electronic databases (Web of Science, PubMed, Cochrane Library, Embase, CNKI, VIP, and Wanfang database) to reach systematic conclusions. Outcome measurements, including therapeutic efficacy, clinical symptoms, and adverse events, were extracted and analyzed statistically.

Ultimately, a total of 10 articles including 662 HBV-C patients were included in this analysis, which indicated that ABMSC therapy could significantly improve liver function in patients with HBV-C in terms of the MELD and Child-Pugh scores, total bilirubin, serum albumin, alanine aminotransferase, aspartate aminotransferase, and coagulation function. Compared with patients receiving routine therapy (RT), those treated with ABMSC and RT combined therapy showed improved clinical symptoms, as represented by increased appetite and reduced fatigue and ascitic fluid and abdominal distension. Moreover, the fibrosis indexes indicated a reduction in liver fibrosis in patients treated with combined therapy according to the improved levels of hyaluronic acid (MD = − 70.47, CI = − 103.72–37.21, P <  0.0001), laminin (MD = − 25.11, CI = − 37.73–12.49, P <  0.0001), type III procollagen (MD = − 22.42, CI = − 34.49–10.34, P = 0.0003), and type IV collagen (MD = − 22.50, CI = − 39.92–5.08, P = 0.01). No obvious adverse events occurred during ABMSC treatment.

ABMSC transplantation via the hepatic artery was safe and effective in treating HBV-C without causing severe adverse events.

• Autologous bone marrow stem cell
• Hepatic artery
• Hepatitis B virus-related cirrhosis
• Meta-analysis
• Routine therapy

• cell therapy
• extracellular vesicles
• liver diseases
• organ printing
• organoids
• scaffolds
• transplantation

• Cell- and Tissue-Based Therapy
• Cell-Free System
• Clinical Trials as Topic
• Genetic Therapy
• Hepatocytes/transplantation
• Humans
• Liver Diseases/therapy
• Stem Cell Transplantation

• Biomarkers
• Gastroenterology
• Microbiome
• Progenitor cells
• Regenerative medicine
• Stem cells
• VSELs

The immunomodulatory potential of mesenchymal stromal cells (MSCs) and regulatory T cells (T‐reg) is well recognized by translational scientists in the field of regenerative medicine and cellular therapies. A wide range of preclinical studies as well as a limited number of human clinical trials of MSC therapies have not only shown promising safety and efficacy profiles but have also revealed changes in T‐reg frequency and function. However, the mechanisms underlying this potentially important observation are not well understood and, consequently, the optimal strategies for harnessing MSC/T‐reg cross‐talk remain elusive. Cell‐to‐cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes, and induction of extracellular vesicles (“exosomes”) have emerged as possible mechanisms by which MSCs produce an immune‐modulatory milieu for T‐reg expansion. Additionally, these two cell types have the potential to complement each other's immunoregulatory functions, and a combinatorial approach may exert synergistic effects for the treatment of immunological diseases. In this review, we critically assess recent translational research related to the outcomes and mechanistic basis of MSC effects on T‐reg and provide a perspective on the potential for this knowledge base to be further exploited for the treatment of autoimmune disorders and transplants.

• T cells
• adult stem cells
• autoimmune disease
• cellular therapy
• cytokines
• immunotherapy
• mesenchymal stem cells
• stromal cells