Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis.

Myeloid malignancies and the microenvironment

The use and effectiveness of hematopoietic stem cell transplantation (HSCT) are limited by lethal complications, i.e., acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively), in which immune cells from the donor attack healthy recipient tissues. GVHD presents both prophylactic and therapeutic challenges, and overall survival is poor. Mesenchymal stem cells (MSCs) show considerable promise in the treatment of GVHD because of their potential immunomodulatory activity. Multiple studies have been performed to explore the possible benefit of MSCs in GVHD, but the results of these studies are sometimes conflicting. Therefore, we performed a systematic review and meta-analysis to estimate the effect of MSC infusion on GVHD treatment and prevention. We systematically searched the MEDLINE (PubMed), Cochrane Library, EMBASE, ClinicalTrials.gov, and SinoMed CBM databases to identify studies published before February 2018 involving patients with hematologic malignancies undergoing HSCT and receiving MSC-based or conventional therapy. We included studies if they reported on the outcomes of interest. Ultimately, 10 studies were selected from among 413 candidates. According to our meta-analyses, compared with conventional treatment, MSC therapy demonstrated substantial improvements in terms of complete response (CR) and overall survival for cGVHD. However, MSC therapy did not show substantial improvements in terms of engraftment, the incidence of aGVHD, relapse, death, death due to relapse, or death due to infection. Subgroup analyses showed that MSCs derived from the umbilical cord (U-MSCs) and MSC infusion after HSCT substantially improved engraftment and cGVHD incidence, whereas MSCs derived from bone marrow (B-MSCs) and MSC infusion before HSCT shows no improvement. In addition, B-MSCs and MSC infusion before HSCT tend to prolong engraftment time, as well as increase the rates of relapse and death. MSC infusion can reduce cGVHD but not aGVHD incidence and showed a positive effect in patients who already had aGVHD. For GVHD prevention, the use of U-MSCs and MSC infusion after HSCT were optimal for reducing cGVHD incidence and promoting engraftment, and might help decrease the incidence rate of relapse and death. However, B-MSCs and MSC infusion before HSCT may be harmful to patients and thus require serious consideration. A lack of robust evidence, owing to the small number of studies and small sample sizes, indicates a need for further high-quality clinical trials including large numbers of patients to validate our findings.

/pdf/the-role-of-mesenchymal-stem-cells-in-hematopoietic-stem-371sfbsn1j.pdf

The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease.

Background
Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft‐versus‐host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune‐mediated disorders. GvHD is one of the first areas in which MSCs were clinically applied, and it is important that the accumulating evidence is systematically reviewed to assess whether their use is favoured.

/pdf/mesenchymal-stromal-cells-as-treatment-or-prophylaxis-for-5cc9y4w4kf.pdf

Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition.

Heterogeneity in Studies of Mesenchymal Stromal Cells to Treat or Prevent Graft-versus-Host Disease: A Scoping Review of the Evidence

Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors' multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups - those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the FGFR1 gene in combination with reduced expression levels of the PPARG and IGF1 genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82-94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the development of aGVHD in the maximal number of patients.

/pdf/analysis-of-results-of-acute-graft-versus-host-disease-2094o4vl6c.pdf

Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation.

We studied the capacity of multipotent mesenchymal stromal cells isolated from human bone marrow (BM) to long-term passaging, cloning, and re-cloning. Initial multipotent mesenchymal stromal cells and cells after gene labeling were studied. Multipotent mesenchymal stromal cells were obtained from donors (13–59 years) and cultured for 7 passages. Third generation lentivector was used for delivery of green fluorescent protein marker gene. The procedure of infection revealed reduced proliferative potential of multipotent mesenchymal stromal cells from elder donors. Hierarchy of precursor cells differing by their proliferative potential was demonstrated in the culture of multipotent mesenchymal stromal cells. Three categories of multipotent mesenchymal stromal cells were identified: mature cells incapable of proliferation (75.7 ± 2.4% population) and cells with low and high proliferative potential (17.6 ± 2.1 and 6.7 ± 0.3%, respectively). The relative content of these cells insignificantly differed from passage to passage. The efficiency of cloning also remains stable, but re-cloning capacity sharply decreased after passage 3 and completely disappeared in multipotent mesenchymal stromal cells after cryopreservation. Thus, cultured multipotent mesenchymal stromal cells represent a heterogeneous and hierarchically organized population and the characteristics of this population depend of the duration of culturing and age of BM donor. This should be taken into account when using multipotent mesenchymal stromal cells in clinical practice.

Proliferative Potential of Multipotent Mesenchymal Stromal Cells from Human Bone Marrow

In the bone marrow of vertebrates, two types of stem cells coexist—hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Hematopoiesis only occurs when these two stem cell types and their descendants interact. The descendants of HSCs supply the body with all the mature blood cells, while MSCs give rise to stromal cells that form a niche for HSCs and regulate the process of hematopoiesis. The studies of hematopoiesis were initially based on morphological observations, later extended by the use of physiological methods, and were subsequently augmented by massive application of sophisticated molecular techniques. The combination of these methods produced a wealth of new data on the organization and functional features of hematopoiesis in the ontogenesis of mammals and humans. This review summarizes the current views on hematopoiesis in mice and humans, discusses the development of blood elements and hematopoiesis in the embryo, and describes how the hematopoietic system works in the adult organism and how it changes during aging.

Hematopoiesis during Ontogenesis, Adult Life, and Aging

Background

Multipotent mesenchymal stromal cells (MSCs) are used for prophylaxis of acute graft-versus-host disease (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Not all samples of MSC are efficient for aGvHD prevention. The suitability of MSCs for aGvHD prophylaxis was studied.



Methods

MSCs were derived from the bone marrow (BM) of HCT donor and cultivated for no more than three passages. The characteristics of donor BM samples including colony-forming unit fibroblast (CFU-F) concentration, growth parameters of MSCs, and the relative expression levels (REL) of different genes were analyzed. MSCs were injected intravenously precisely at the moment of blood cell reconstitution.



Results

MSCs infusion induced a significant threefold decrease in aGvHD development and improved overall survival compared with the standard prophylaxis group. In ineffective MSC samples (9.4%), a significant decrease in total cell production and the REL of CSF1, FGFR1, and PDGFRB was observed. In all studied BM samples, the cumulative MSC production and CFU-F concentrations decreased with age. The expression levels of FGFR2, PPARG, and VEGF differed by age.



Conclusions

A universal single indicator for the prediction of MSC eligibility for aGvHD prophylaxis was not identified. A multiparameter mathematical model for selecting MSC samples effective for the prevention of aGvHD was proposed.

Analysis of multipotent mesenchymal stromal cells used for acute graft-versus-host disease prophylaxis.

Bone marrow (BM) derived adult multipotent mesenchymal stromal cells (MMSCs) and fibroblast colony-forming units (CFU-Fs) of 20 patients with acute myeloid leukemia (AML) and 15 patients with acute lymphoblastic leukemia (ALL) before and during 1 year after receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) were studied. The growth characteristics of MMSCs of all patients before allo-HSCT were not altered; however, relative expression level (REL) of some genes in MMSCs, but not in CFU-Fs, from AML and ALL patients significantly changed. After allo-HSCT, CFU-F concentration and MMSC production were significantly decreased for 1 year; REL of several genes in MMSCs and CFU-F-derived colonies were also significantly downregulated. Thus, chemotherapy that was used for induction of remission did not impair the function of stromal precursors, but gene expression levels were altered. Allo-HSCT conditioning regimens significantly damaged MMSCs and CFU-Fs, and the effect lasted for at least 1 year.

Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation.

Nataliya Petinati

Papers

Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation.

Proliferative Potential of Multipotent Mesenchymal Stromal Cells from Human Bone Marrow

Hematopoiesis during Ontogenesis, Adult Life, and Aging

Analysis of multipotent mesenchymal stromal cells used for acute graft-versus-host disease prophylaxis.

Alterations of the bone marrow stromal microenvironment in adult patients with acute myeloid and lymphoblastic leukemias before and after allogeneic hematopoietic stem cell transplantation.