Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

Dander, Erica; Lucchini, Giovanna; Vinci, Paola; Introna, Martino; Masciocchi, Francesca; Perseghin, Paolo; Balduzzi, Adriana; Bonanomi, Sonia; Longoni, Daniela; Gaipa, Giuseppe; Belotti, Daniela; Parma, Matteo; Algarotti, Alessandra; Capelli, Chiara; Golay, Joseé; Rovelli, Attilio; Rambaldi, Alessandro; Biondi, Andrea; Biagi, Ettore; D’Amico, Giovanna

doi:10.1038/leu.2011.384

Cited by 61 publications

(51 citation statements)

References 15 publications

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“…MSC provide an excellent cell source for cellular therapies to treat bone and cartilage disorders [91, 92], myocardial infarction, stroke [93, 94], rheumatoid arthritis [95], acute lung injury [96, 97], graft-versus-host disease [98] and skin-graft rejection [99] among others. The use of MSC for tissue repair requires the migration and homing to the site of damaged tissue and it has been shown that both the migratory and proliferation potential of these cells are affected by CDH2 and CDH11 [100, 101].…”

Section: The Role Of Cdh2 and Cdh11 In Mesenchymal Stem Cell Diffementioning

confidence: 99%

CDH2 and CDH11 act as regulators of stem cell fate decisions

2015

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Accumulating evidence suggests that the mechanical and biochemical signals originating from cell-cell adhesion are critical for stem cell lineage specification. In this review, we focus on the role of cadherin mediated signaling in development and stem cell differentiation, with emphasis on two well-known cadherins, cadherin-2 (CDH2) (N-cadherin) and cadherin-11 (CDH11) (OB-cadherin). We summarize the existing knowledge regarding the role of CDH2 and CDH11 during development and differentiation in vivo and in vitro. We also discuss engineering strategies to control stem cell fate decisions by fine-tuning the extent of cell-cell adhesion through surface chemistry and microtopology. These studies may be greatly facilitated by novel strategies that enable monitoring of stem cell specification in real time. We expect that better understanding of how intercellular adhesion signaling affects lineage specification may impact biomaterial and scaffold design to control stem cell fate decisions in three-dimensional context with potential implications for tissue engineering and regenerative medicine.

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Section: The Role Of Cdh2 and Cdh11 In Mesenchymal Stem Cell Diffementioning

confidence: 99%

CDH2 and CDH11 act as regulators of stem cell fate decisions

2015

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“…MSCs were isolated and expanded ex vivo from bone marrow aspirates, as previously described [22]. Briefly, total nucleated cells were isolated from the washouts of sealed bone marrow collection bags and filters.…”

Section: Isolation and Culture Of Human Mscsmentioning

confidence: 99%

Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma

et al. 2014

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Microglia/macrophages (M) are major contributors to postinjury inflammation, but they may also promote brain repair in response to specific environmental signals that drive classic (M1) or alternative (M2) polarization. We investigated the activation and functional changes of M in mice with traumatic brain injuries and receiving intracerebroventricular human bone marrow mesenchymal stromal cells (MSCs) or saline infusion. MSCs upregulated Ym1 and Arginase-1 mRNA (p<0.001), two M2 markers of protective M polarization, at 3 and 7 d postinjury, and increased the number of Ym1 + cells at 7 d postinjury (p<0.05). MSCs reduced the presence of the lysosomal activity marker CD68 on the membrane surface of CD11b-positive M (p<0.05), indicating reduced phagocytosis. MSC-mediated induction of the M2 phenotype in M was associated with early and persistent recovery of neurological functions evaluated up to 35 days postinjury (p<0.01) and reparative changes of the lesioned microenvironment. In vitro, MSCs directly counteracted the proinflammatory response of primary murine microglia stimulated by tumor necrosis factor-α+interleukin 17 or by tumor necrosis factor-α + interferon-γ and induced M2 proregenerative traits, as indicated by the downregulation of inducible nitric oxide synthase and upregulation of Ym1 and CD206 mRNA (p < 0.01). In conclusion, we found evidence that MSCs can drive the M transcriptional environment and induce the acquisition of an early, persistent M2-beneficial phenotype both in vivo and in vitro. Increased Ym1 expression together with reduced in vivo phagocytosis suggests M selection by MSCs towards the M2a subpopulation, which is involved in growth stimulation and tissue repair.

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“…Despite our vast knowledge of the effects of MSCs on immune cells in vitro and the data from preclinical models [2], few reports have shed light on the effects of MSCs on the patient's immune system [5]. Such knowledge is essential for the treatment of GVHD as it is an immune-mediated reaction involving T-cells [1], natural killer (NK)-cells [6], dendritic cells (DCs) [7], and monocytes [8], which could all be impacted by MSCs [2].…”

Section: Introductionmentioning

confidence: 99%

Alterations in the Cellular Immune Compartment of Patients Treated with Third-Party Mesenchymal Stromal Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2013

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Adoptive transfer of third-party mesenchymal stromal cells (MSCs) has emerged as a promising tool for the treatment of steroid-refractory graft-versus-host disease (GVHD). Despite numerous in vitro studies and preclinical models, little is known about their effects on the patients' immune system. We assessed immune alterations in the T-cell, B-cell, natural killer cell, dendritic cell, and monocytic compartments of steroid-refractory GVHD patients 30, 90, and 180 days after MSC (n = 6) or placebo (n = 5) infusion, respectively. Infused MSCs were bioactive as suggested by the significant reduction in epithelial cell death, which represents a biomarker for acute GVHD. There were several indications that MSCs shift the patients' immune system toward a more tolerogenic profile. Most importantly, infusion of MSCs was associated with increased levels of regulatory (forkhead box P3 (FOXP3)+ and interleukin (IL)-10+) T-cells, reduced pro-inflammatory IL-17+ T(Th17)-cells, and skewing toward type-2 T-helper cell responses. Furthermore, IL-2, which has been recently shown to exert a positive immune modulating effect in GVHD patients, was higher in the MSC patients at all evaluated time points during 6 months after MSC-infusion. Overall, our findings will contribute to the refinement of monitoring tools, for assessing MSC treatment-efficacy and increase our understanding regarding the MSCs' in vivo effects.

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Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring

Cited by 61 publications

References 15 publications

CDH2 and CDH11 act as regulators of stem cell fate decisions

CDH2 and CDH11 act as regulators of stem cell fate decisions

Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma

Alterations in the Cellular Immune Compartment of Patients Treated with Third-Party Mesenchymal Stromal Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

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