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Mesenchymal stromal cells in hematopoietic cell transplantation.

ABSTRACT: Mesenchymal stromal cells (MSCs) are widely recognized to possess potent immunomodulatory activity, as well as to stimulate repair and regeneration of diseased or damaged tissue. These fundamental properties suggest important applications in hematopoietic cell transplantation. Although the mechanisms of therapeutic activity in vivo are yet to be fully elucidated, MSCs seem to suppress lymphocytes by paracrine mechanisms, including secreted mediators and metabolic modulators. Most recently, host macrophage engulfment of apoptotic MSCs has emerged as an important contributor to the immune suppressive microenvironment. Although bone marrow-derived MSCs are the most commonly studied, the tissue source of MSCs may be a critical determinant of immunomodulatory function. The key application of MSC therapy in hematopoietic cell transplantation is to prevent or treat graft-versus-host disease (GVHD). The pathogenesis of GVHD reveals multiple potential targets. Moreover, the recently proposed concept of tissue tolerance suggests a new possible mechanism of MSC therapy for GVHD. Beyond GVHD, MSCs may facilitate hematopoietic stem cell engraftment, which could gain greater importance with increasing use of haploidentical transplantation. Despite many challenges and much doubt, commercial MSC products for pediatric steroid-refractory GVHD have been licensed in Japan, conditionally licensed in Canada and New Zealand, and have been recommended for approval by an FDA Advisory Committee in the United States. Here, we review key historical data in the context of the most salient recent findings to present the current state of MSCs as adjunct cell therapy in hematopoietic cell transplantation.

SUBMITTER: Burnham AJ

PROVIDER: S-EPMC7686890 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Mesenchymal stromal cells in hematopoietic cell transplantation.

Burnham Andre J AJ Daley-Bauer Lisa P LP Horwitz Edwin M EM

Blood advances 20201101 22

Mesenchymal stromal cells (MSCs) are widely recognized to possess potent immunomodulatory activity, as well as to stimulate repair and regeneration of diseased or damaged tissue. These fundamental properties suggest important applications in hematopoietic cell transplantation. Although the mechanisms of therapeutic activity in vivo are yet to be fully elucidated, MSCs seem to suppress lymphocytes by paracrine mechanisms, including secreted mediators and metabolic modulators. Most recently, host ...[more]

PMID: 33232479

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Project description:IntroductionPoor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT.MethodsWe prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330).ResultsWithin 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 109/L, Hb > 80g/L and platelet count > 20 x 109/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 109/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention.DiscussionIn conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.

Project description:BackgroundHematopoietic stem cell transplantation (HSCT) is a standard therapy strategy for most malignant disorders in children. However, transplant-related pneumonia remains a major therapy challenge and mesenchymal stromal cells (MSCs) are rarely reported in HSCT-related pneumonia. The aim of our study was to assess the efficacy of MSC for HSCT-related pneumonia in children.MethodsWe retrospectively retrieved HSCT-related (severe and non-severe) pneumonia cases (aged < 18 years), which underwent MSC treatment (MSC group) or non-MSC treatment (non-MSC group) in Guangzhou Women and Children's Medical Center, from December 2017 to December 2019. We investigated outcomes of the two different treatments among severe cases and non-severe cases, respectively. The primary endpoints were differences in overall cure rate and time to cure between MSC and non-MSC groups. The secondary endpoints were 180-day overall survival and cumulative cure rate.ResultsFinally, 31 severe pneumonia cases (16 in MSC group, 15 in non-MSC group) and 76 non-severe cases (31 in MSC group, 45 in non-MSC group) were enrolled in this study. Among severe pneumonia cases, overall cure rate in MSC group was significant higher than that in non-MSC group (12[75.0%] vs. 5[33.3%]; OR = 6.00, 95% CI [1.26-28.5]; p = 0.020); the time (days) to cure in MSC group was dramatically reduced compared with that in non-MSC group (36 [19-52] vs. 62 [42-81]; OR = 0.32, 95% CI [0.12-0.88]; p = 0.009); the 180-day overall survival in MSC group was better than that in non-MSC group (74.5% [45.4-89.6] vs. 33.3% [12.2-56.4]; p = 0.013). Among non-severe pneumonia cases, the time (days) to cure in MSC group was notably decreased compared with that in non-MSC group (28 [24-31] vs. 33 [26-39]; OR = 0.31, 95% CI [0.18-0.56]; p = 0.003). Compared with non-MSC group, MSC-treated patients achieved significant improvements of cumulative cure rate not only in severe pneumonia cases (p = 0.027), but also in non-severe cases (p < 0.001).ConclusionsThis study revealed that MSC treatment could contribute to improving outcomes in children with pneumonia post-HSCT, especially in severe cases. These findings suggest MSC treatment as a promising therapy for HSCT-related pneumonia in children.

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Mesenchymal stromal cells in hematopoietic cell transplantation.

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Mesenchymal stromal cells in hematopoietic cell transplantation.

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