Background: Blood vessel formation is fundamental to development, while its dysregulation can contribute to serious disease. Expectations are that hundreds of millions of individuals will benefit from therapeutic developments in vascular biology. MSCs are central to the three main vascular repair mechanisms. Sources of data: Key recent published literature and ClinicalTrials.gov. Areas of agreement: MSCs are heterogeneous, containing multi-lineage stem and partly differentiated progenitor cells, and are easily expandable ex vivo. There is no single marker defining native MSCs in vivo. Their phenotype is strongly determined by their specific microenvironment. Bone marrow MSCs have skeletal stem cell properties. Having a perivascular/vascular location, they contribute to vascular formation and function and might be harnessed to regenerate a blood supply to injured tissues. Areas of controversy: These include MSC origin, phenotype and location in vivo and their ability to differentiate into functional cardiomyocytes and endothelial cells or act as vascular stem cells. In addition their efficacy, safety and potency in clinical trials in relation to cell source, dose, delivery route, passage and timing of administration, but probably even more on the local preconditioning and the mechanisms by which they exert their effects.

The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential

PurposeAlthough mesenchymal stromal cells (MSCs) possess immunomodulatory properties and exhibit promising efficacy against chronic graft-versus-host disease (cGVHD), little is known about the efficacy of MSCs in the prophylaxis of cGVHD after HLA-haploidentical hematopoietic stem-cell transplantation (HLA-haplo HSCT).Patients and MethodsIn this multicenter, double-blind, randomized controlled trial, we investigated the incidence and severity of cGVHD among patients, and the changes in T, B, and natural killer (NK) cells after the repeated infusion of MSCs.ResultsThe 2-year cumulative incidence of cGVHD in the MSCs group was 27.4% (95% CI, 16.2% to 38.6%), compared with 49.0% (95% CI, 36.5% to 61.5%) in the non-MSCs control group (P = .021). Seven patients in the non-MSCs control group had severe lung cGVHD, but no patients in the MSCs group developed typical lung cGVHD (P = .047). After the MSC infusions, increasing memory B lymphocytes and regulatory T cells, as well as the ratio of type 1 T helper to t...

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Phase II Multicenter, Randomized, Double-Blind Controlled Study of Efficacy and Safety of Umbilical Cord–Derived Mesenchymal Stromal Cells in the Prophylaxis of Chronic Graft-Versus-Host Disease After HLA-Haploidentical Stem-Cell Transplantation

Mesenchymal stromal cells (MSCs) are attractive agents for the prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) However, safety concerns remain about their clinical application In this study, we explored whether extracellular vesicles released from human umbilical cord-derived MSCs (hUC-MSC-EVs) could prevent aGVHD in a mouse model of allo-HSCT hUC-MSC-EVs were intravenously administered to recipient mice on days 0 and 7 after allo-HSCT, and the prophylactic effects of hUC-MSC-EVs were assessed by observing the in vivo manifestations of aGVHD, histologic changes in target organs, and recipient mouse survival We evaluated the effects of hUC-MSC-EVs on immune cells and inflammatory cytokines by flow cytometry and ProcartaPlex™ Multiplex Immunoassays, respectively The in vitro effects of hUC-MSC-EVs were determined by mitogen-induced proliferation assays hUC-MSC-EVs alleviated the in vivo manifestations of aGVHD and the associat

Extracellular Vesicles Released from Human Umbilical Cord-Derived Mesenchymal Stromal Cells Prevent Life-Threatening Acute Graft-Versus-Host Disease in a Mouse Model of Allogeneic Hematopoietic Stem Cell Transplantation.

Li J, Ezzelarab MB, Cooper DKC. Do mesenchymal stem cells function across species barriers? Relevance for xenotransplantation. Xenotransplantation 2012; 19: 273–285. © 2012 John Wiley & Sons A/S.

Abstract:  Background:  Allogeneic mesenchymal stem (stromal) cells (MSC) are a promising therapy for various pathological conditions. Genetically modified pig MSC have been demonstrated to downregulate the human T-cell response to pig antigens in vitro. Before genetically modified pig MSC can be used clinically, however, evidence needs to be provided to indicate whether they will survive in a human (xenogeneic) host.

Literature Search and Results:  A literature search through the end of 2011 identified 94 reports of the in vivo cross-species administration of MSC in a variety of experimental models. The majority (n = 89) involved the use of human MSC in various other species, with an occasional study using pig, rat, or guinea-pig MSC. When human MSC were used, they were largely derived from the bone marrow, adipose tissue, or umbilical cord blood. The routes of administration were varied, although almost half of the studies utilized the intravenous route. In 88 experiments (93.6%), there was evidence that the MSC engrafted and functioned across the species barrier, and in only six cases (6.4%) was there evidence of failure to function. Importantly, MSC function was confirmed in several different cross-species models. For example, human MSC functioned in no fewer than seven different recipient species.

Conclusions:  The data provided by this literature search strengthen the hypothesis that pig MSC will function satisfactorily in a different species, for example, humans. The data also suggest that our own in vitro observations on the efficacy of pig MSC in downregulating the strength of the human T-cell response to pig antigens will likely be reproduced in vivo in pre-clinical large animal models and in clinical trials.

Do mesenchymal stem cells function across species barriers? Relevance for xenotransplantation

Mesenchymal stromal cells (MSCs) are multipotent stem cells well known for repairing tissue, supporting hematopoiesis, and modulating immune and inflammation response. These outstanding properties make MSCs as an attractive candidate for cellular therapy in immune-based disorders, especially hematopoietic stem cell transplantation (HSCT). In this review, we outline the progress of MSCs in preventing and treating engraftment failure (EF), graft-versus-host disease (GVHD) following HSCT and critically discuss unsolved issues in clinical applications.

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The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation.

Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery It has been postulated that MSCs have hematopoiesis-supportive properties Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT Seven patients received UCB and third-party UCB-MSCs Hematopoietic recovery and transplantation outcomes were compared with historic controls There was no acute toxicity associated with the infusion of MSCs The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=003) The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=026) In addition, there was no engraftment failure in the MSC group The incidence of acute and chronic GVHD was comparable between the two groups However, veno-occlusive disease and TRM did not occur in the MSC group Third-party UCB-MSCs infusion was safe and feasible MSCs may also enhance the engraftment of UCBT and prevent rejection In addition, MSCs may have a role in decreasing TRM Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse

Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation

Purpose: The risk of invasive fungal infection is greater for allogeneic hematopoietic stem cell transplantation (HSCT) than for autologous transplantation. Therefore, many transplantation centers use antifungal prophylaxis for allogeneic HSCT, however, there exists no standard guidelines or consensus regarding autologous HSCT. Materials and Methods: A prospective double-blind randomized study was conducted in autologous HSCT recipients who were divided into prophylaxis and empirical treatment groups, and we investigated the efficacy of itra conazole prophylaxis in pediatric autologous HSCT. Results: Total 87 autologous HSCT episodes in 55 children with high-risk solid tumors were studied. No invasive fungal infections occurred in either group. However, patients in the prophylaxis group had a significantly shorter duration of fever ( p < 0.05) and received antibacterial treatment of shorter duration (p < 0.05) with fewer numbers of antibiotics (p < 0.05 for the use of second line antibiotics) than those in the empirical group. No significant additional adverse events were found with itraconazole prophylaxis. Conclusion: Although beneficial effects such as a shorter duration of fever and reduced need for antibiotic use were observed in the prophylaxis group, the results were not sufficient to draw a definite recommendation about the routine use of antifungal prophylaxis in pediatric autologous HSCT recipients with highrisk solid tumors (Trial registration: NCT00336531).

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Efficacy of Itraconazole Prophylaxis for Autologous Stem Cell Transplantation in Children with High-Risk Solid Tumors: A Prospective Double-Blind Randomized Study

Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSC) facilitate the engraftment of human (h) hematopoietic stem cells when transplanted simultaneously in animal and human studies. However, the type of MSCs that preferentially enhance the engraftment of HSCs is unknown. Recent studies have shown that MSCs derived from a single source are heterogeneous in terms of cell size, morphology, proliferation rate, and differentiation potential. This study was designed to investigate the properties of UCB-MSCs, which influence the engraftment of hHSCs in a NOD/SCID mouse model. We categorized MSCs as being the most effective (UCB-352 MSCs) or the least effective (UCB-156 MSCs) at promoting the homing and engraftment of HSCs, and compared the characteristics of these 2 MSC populations. We observed that the 2 populations showed differences in characteristics typical of immature MSCs, and related to proliferation potential. We showed that UCB-352 MSCs, which proliferate quickly, preferentially enhanced the engraftment of HSCs in NOD/SCID mice. In addition, we observed differences in the pattern of both PODXL and Oct4 expression, and in the levels of cytokines such as SDF-1 and SCF using flow cytometry and membrane arrays. The more effective UCB-352 MSCs expressed higher levels of PODXL and Oct4, which were associated with immaturity, than did the UCB-156 MSCs. Furthermore, UCB-352 cells secreted greater levels of SDF-1 and SCF, both of which are required for hematopoiesis. We propose that the proliferation potential of UCB-MSCs, coupled with their immature characteristics, may serve as a novel standard to promote the homing and engraftment of HSCs.

Correlation Between the Immature Characteristics of Umbilical Cord Blood–Derived Mesenchymal Stem Cells and Engraftment of Hematopoietic Stem Cells in NOD/SCID Mice

Cotransplantation of Third Party Umbilical Cord Blood Mesenchymal Stem Cells to Promote Engraftment in Pediatric Recipients of Unrelated Donor Umbilical Cord Blood

Correspondence to: Jin-A Jung https://orcid.org/0000-0002-4243-6983 Department of Pediatrics, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-gu, Busan 49201, Korea Tel: +82-51-240-5617, Fax: +82-51-242-2765, Email: jina1477@dau.ac.kr Received: July 6, 2021 Revised: October 14, 2021 Accepted: October 26, 2021 © 2022 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/). 호흡곤란으로 내원한 1개월 영아에서 진단된 상기도 혈관종 1예

Hee Won Cheuh

Papers

Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation

Efficacy of Itraconazole Prophylaxis for Autologous Stem Cell Transplantation in Children with High-Risk Solid Tumors: A Prospective Double-Blind Randomized Study

Correlation Between the Immature Characteristics of Umbilical Cord Blood–Derived Mesenchymal Stem Cells and Engraftment of Hematopoietic Stem Cells in NOD/SCID Mice

Cotransplantation of Third Party Umbilical Cord Blood Mesenchymal Stem Cells to Promote Engraftment in Pediatric Recipients of Unrelated Donor Umbilical Cord Blood

A case of airway hemangioma in a 1-month-old infant with dyspnea