• Allogeneic hematopoietic cell transplantation
• GVHD
• HLA mismatch
• Mesenchymal stromal cells
• Prevention

• Humans
• Graft vs Host Disease/prevention & control
• Hematopoietic Stem Cell Transplantation/methods
• Hematopoietic Stem Cell Transplantation/adverse effects
• Transplantation Conditioning/methods
• Double-Blind Method
• Male
• Adult
• Female
• Middle Aged
• Mesenchymal Stem Cells
• Mesenchymal Stem Cell Transplantation/methods
• Unrelated Donors
• Transplantation, Homologous/methods
• HLA Antigens/immunology
• HLA Antigens/metabolism
• Adolescent
• Aged
• Young Adult

• Fonds De La Recherche Scientifique - FNRS
• Fondation contre le Cancer
• Université de Liège
• Centre Hospitalier Universitaire de Liège
• Fonds Léon Fredericq

• GVHD
• engraftment
• mesenchymal cells
• tumorigenesis

Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date.

In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field’s progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed.

In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future.

The online version contains supplementary material available at 10.1186/s13287-022-02751-0.

• Clinical trials
• Graft-versus-host disease
• Mesenchymal stem cells

• Cell therapy
• HLA-G polymorphism
• Hematopoietic stem cell transplantation
• Immunomodulation
• human leukocyte antigen G gene

Multipotent mesenchymal stromal cells (MSCs) are widely used in the clinic due to their unique properties, namely, their ability to differentiate in all mesenchymal directions and their immunomodulatory activity. Healthy donor MSCs were used to prevent the development of acute graft vs host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). The administration of MSCs to patients was not always effective. The MSCs obtained from different donors have individual characteristics. The differences between MSC samples may affect their clinical efficacy.

To study the differences between effective and ineffective MSCs.

MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution. Aliquots of 52 MSC samples that were administered to patients were examined, and the same cells were cultured in the presence of peripheral blood mononuclear cells (PBMCs) from a third-party donor or treated with the pro-inflammatory cytokines IL-1β, IFN and TNF. Flow cytometry revealed the immunophenotype of the nontreated MSCs, the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines. The proportions of CD25-, CD146-, CD69-, HLA-DR- and PD-1-positive CD4+ and CD8+ cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined.

Differences in the immunophenotypes of effective and ineffective MSCs were observed. In the effective samples, the mean fluorescence intensity (MFI) of HLA-ABC, HLA-DR, CD105, and CD146 was significantly higher. After MSCs were treated with IFN or cocultured with PBMCs, the HLA-ABC, HLA-DR, CD90 and CD54 MFI showed a stronger increase in the effective MSCs, which indicated an increase in the immunomodulatory activity of these cells. When PBMCs were cocultured with effective MSCs, the proportions of CD4+ and CD8+central memory cells significantly decreased, and the proportion of CD8+CD146+ lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD; in addition, the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples. The proportion of CD4+CD146+ lymphocytes increased only when cocultured with the inefficient samples.

For the first time, differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective. Thus, it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.

• Multipotent mesenchymal stromal cells
• Acute graft vs host disease
• Immunophenotype
• Lymphocytes
• Immunomodulation
• Pro-inflammatory cytokines

Graft-versus-host disease (GvHD) is the main life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty to 80% of GvHD patients do not respond to first-line treatment and a second-line treatment is not universally established. Based on their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed for the prevention and the treatment of GvHD in patients undergoing HSCT. Unfortunately, previous studies reported conflicting results regarding the prophylactic and therapeutic effects of MSC for GvHD. Consequently, we carried out a meta-analysis to clarify whether MSC administration can improve the dismal outcome of these patients.

We carried out a systematic review and selected studies (2004–2019) reporting data about the administration of allogeneic MSC for the prevention (n = 654 patients) or treatment of acute (n = 943 patients) or chronic (n = 76 patients) GvHD after HSCT. Our primary outcome was overall survival at the last follow-up. The secondary outcomes were the response and development of GvHD. Subgroup analyses included age, MSC dose, first infusion day after HSCT, number of organs and organ-specific involvement, acute GvHD grade (I–IV), and chronic GvHD grade (limited or extensive).

Patients infused with MSC for GvHD prophylaxis showed a 17% increased overall survival (95% CI, 1.02–1.33) and a reduced incidence of acute GvHD grade IV (RR = 0.22; 95% CI, 0.06–0.81) and chronic GvHD (RR = 0.64; 95% CI, 0.47–0.88) compared with controls. Overall survival of acute GvHD patients (0.50; 95% CI, 0.41–0.59) was positively correlated with MSC dose (P = 0.0214). The overall response was achieved in 67% (95% CI, 0.61–0.74) and was complete in 39% (95% CI, 0.31–0.48) of acute patients. Organ-specific response was higher for the skin. Twenty-two percent (95% CI, 0.16–0.29) of acute patients infused with MSC developed chronic GvHD. Sixty-four percent (95% CI, 0.47–0.80) of chronic patients infused with MSC survived; the overall response was 66% (95% CI, 0.55–0.76) and was complete in 23% (95% CI 0.12–0.34) of patients.

Our meta-analysis indicates that allogeneic MSC could be instrumental for the prophylaxis and treatment of GvHD. Future trials should investigate the effect of the administration of MSC as an adjuvant therapy for the treatment of patients with GvHD from the onset of the disease.

• Acute graft-versus-host disease
• Cell therapy
• Chronic graft-versus-host disease
• Hematopoietic stem cell transplantation
• Mesenchymal stromal cells
• Meta-analysis
• Prophylaxis
• Treatment

• Adverse events
• Mesenchymal stem cells
• Safety
• Systematic review

• bone marrow
• good manufacturing practices
• graft versus host disease
• immunomodulation
• mesenchymal stromal cells

The therapeutic repertoire for life-threatening inflammatory conditions like sepsis, graft-versus-host reactions, or colitis is very limited in current clinical practice and, together with chronic ones, like the osteoarthritis, presents growing economic burden in developed countries. This urges the development of more efficient therapeutic modalities like the mesenchymal stem cell-based approaches. Despite the encouraging in vivo data, however, clinical trials delivered ambiguous results. Since one of the typical features of inflamed tissues is decreased oxygenation, the success of cellular therapy in inflammatory pathologies seems to be affected by the impact of oxygen depletion on transplanted cells. Here, we examine our current knowledge on the effect of hypoxia on the physiology of bone marrow-derived mesenchymal stromal cells, one of the most popular tools of practical cellular therapy, in the context of their immune-modulatory capacity.

• Graft-versus-host disease
• Mesenchymal stem cells
• Meta-analysis
• Stem cell transplantation

• Animals
• Graft vs Host Disease/prevention & control
• Graft vs Host Disease/therapy
• Hematopoietic Stem Cell Transplantation/methods
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/physiology

• National Natural Science Foundation of China
• National Key Research and Development Program of China

• clinical transition
• immune disorders
• mesenchymal stem cell

• Cell Differentiation
• Humans
• Immune System Diseases/immunology
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/physiology
• Randomized Controlled Trials as Topic
• Regenerative Medicine

• Acute Disease
• Chronic Disease
• Graft vs Host Disease/epidemiology
• Graft vs Host Disease/therapy
• Hematologic Neoplasms/mortality
• Hematologic Neoplasms/therapy
• Hematopoietic Stem Cell Transplantation/adverse effects
• Humans
• Incidence
• Mesenchymal Stem Cell Transplantation/mortality
• Randomized Controlled Trials as Topic
• Recurrence
• beta-Thalassemia/therapy

• RP-PG-0310-1003 Department of Health

• autoimmune diseases
• immune-related diseases
• immunomodulation
• immunomodulatory therapy
• inflammation
• inflammatory diseases
• mesenchymal stem cell
• neurologic diseases

• Graft-versus-host disease
• Hematopoietic stem cell transplantation
• Mesenchymal stromal cells
• Meta-analysis
• Prophylaxis
• Randomized controlled trials

Multipotent mesenchymal stromal cells (MSCs) participate in the formation of bone marrow niches for hematopoietic stem cells. Donor MSCs can serve as a source of recovery for niches in patients with graft failure (GF) after allogeneic bone marrow (BM) transplantation. Since only few MSCs reach the BM after intravenous injection, MSCs were implanted into the iliac spine. For 8 patients with GF after allo-BMT, another hematopoietic stem cell transplantation with simultaneous implantation of MSCs from their respective donors into cancellous bone was performed. BM was aspirated from the iliac crest of these patients at 1-2, 4-5, and 9 months after the intraosseous injection of donor MSCs. Patients' MSCs were cultivated, and chimerism was determined. In 6 out of 8 patients, donor hematopoiesis was restored. Donor cells (9.4 ± 3.3%) were detected among MSCs. Thus, implanted MSCs remain localized at the site of administration and do not lose the ability to proliferate. These results suggest that MSCs could participate in the restoration of niches for donor hematopoietic cells or have an immunomodulatory effect, preventing repeated rejection of the graft. Perhaps, intraosseous implantation of MSCs contributes to the success of the second transplantation of hematopoietic stem cells and patient survival.

• antigens of major histocompatibility complex
• interferon γ (IFNγ)
• multipotent mesenchymal stromal cells
• relative gene expression
• suppression of lymphocyte proliferation

• acute graft-versus-host disease prophylaxis
• colony-forming unit fibroblast
• gene expression
• mesenchymal stromal cell