ORCID Profile
0000-0003-2407-236X
Current Organisation
King's College London
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Publisher: The American Association of Immunologists
Date: 09-2007
DOI: 10.4049/JIMMUNOL.179.5.2824
Abstract: Although it has been widely demonstrated that human mesenchymal stem cells exert potent immunosuppressive effects, there is little information as to whether more mature mesenchymal stromal cells (SC) share the same property. Accordingly, we set out to test the ability of SC from different human tissues to inhibit the proliferation of PBMC following polyclonal stimuli. Chondrocytes, as well as fibroblasts from synovial joints, lung, and skin, were used as a source of SC. Irrespective of their differentiation potential and/or content of progenitor cells, SC from all tissues exhibited antiproliferative functions. This was in marked contrast to parenchymal cells. Although SC did not interfere with early T lymphocyte activation, they arrested stimulated T cells in the G0/G1 phase of the cell cycle and rescued them from apoptosis. In addition, IFN-γ and TNF-α production were reduced. We observed that the inhibitory effect is ultimately mediated by soluble factors, the production of which requires SC to be licensed in an inflammatory environment by cell contact. We conclude that the immunosuppressive effect of mesenchymal cells is not confined to multipotent stem cells, but is a fundamental characteristic of all stroma. Our data suggest that SC, appropriately licensed, regulate T cell homeostasis.
Publisher: Wiley
Date: 2001
DOI: 10.1046/J.1365-2141.2001.02519.X
Abstract: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T-cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52.6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14.5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV-negative patients survival at 5 years was 60% vs. 42% in CMV-positive patients (P = 0.006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV-seronegative recipients of MUD allografts, but in CMV-seropositive patients this approach is associated with an increased non-relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.
Publisher: Future Medicine Ltd
Date: 11-2014
DOI: 10.2217/RME.14.60
Abstract: Aim: Umbilical cord contains, within Wharton's jelly (WJ), multipotent mesenchymal stromal/stem cells (MSCs) of fetal origin that can be isolated and expanded in vitro with a minimal manipulation and very high efficiency. Our aim was to develop a highly reproducible protocol that has the unique potential to be scaled up and adapted to cGMP requirements for the use in cellular therapy. Results: We found that derivation of WJ MSCs under defined conditions in low oxygen resulted in several folds higher populations of MSCA-1 + cells (6.0–19.2%) when compared with WJ MSCs derived in the presence of serum (0.1–2.8%) or clinical-grade bone marrow (BM) MSCs cultured under atmospheric O 2 (20%). We demonstrate that WJ MSCs derived following our protocol display antiproliferative activity similar to clinical-grade BM MSCs. We also show that these WJ MSCs can be differentiated into adipo-, chondro- and osteo-genic lineages. Conclusion: Easy accessibility, abundance and genetic ‘naivety’ make WJ MSCs logistically a more attractive source for clinical applications than BM MSCs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2007
Publisher: American Society of Hematology
Date: 02-2008
DOI: 10.1182/BLOOD-2007-03-082800
Abstract: Osteoblasts are a key component in the regulation of the hematopoietic stem cell (HSC) niche. Manipulating osteoblast numbers results in a parallel change in HSC numbers. We tested the activity of strontium (Sr), a bone anabolic agent that enhances osteoblast function and inhibits osteoclast activity, on hematopoiesis. In vitro treatment of primary murine osteoblasts with Sr increased their ability to form bone nodules, and in vivo it increased osteoblast number, bone volume, and trabecular thickness and decreased trabecular pattern factor. However, the administration of Sr had no influence on primitive HSCs, although the number of hematopoietic progenitors was higher than in control cells. When Sr-treated mice were used as donors for HSC transplantation, no difference in the engraftment ability was observed, whereas hematopoietic recovery was delayed when they were used as recipients. Despite the changes in osteoblast numbers, no increment in the number of N-cadherin+ osteoblasts and N-cadherin transcripts could be detected in Sr-treated mice. Therefore, increasing the overall number and function of osteoblasts without increasing N-cadherin+ cells is not sufficient to enhance HSC quantity and function. Our study further supports the notion that N-cadherin+ osteoblasts are fundamental in the hematopoietic niche.
Publisher: American Society of Hematology
Date: 03-02-2011
DOI: 10.1182/BLOOD-2010-05-282855
Abstract: Osteoblasts play a crucial role in the hematopoietic stem cell (HSC) niche however, an overall increase in their number does not necessarily promote hematopoiesis. Because the activity of osteoblasts and osteoclasts is coordinately regulated, we hypothesized that active bone-resorbing osteoclasts would participate in HSC niche maintenance. Mice treated with bisphosphonates exhibited a decrease in proportion and absolute number of Lin−cKit+Sca1+ Flk2− (LKS Flk2−) and long-term culture–initiating cells in bone marrow (BM). In competitive transplantation assays, the engraftment of treated BM cells was inferior to that of controls, confirming a decrease in HSC numbers. Accordingly, bisphosphonates abolished the HSC increment produced by parathyroid hormone. In contrast, the number of colony-forming-unit cells in BM was increased. Because a larger fraction of LKS in the BM of treated mice was found in the S/M phase of the cell cycle, osteoclast impairment makes a proportion of HSCs enter the cell cycle and differentiate. To prove that HSC impairment was a consequence of niche manipulation, a group of mice was treated with bisphosphonates and then subjected to BM transplantation from untreated donors. Treated recipient mice experienced a delayed hematopoietic recovery compared with untreated controls. Our findings demonstrate that osteoclast function is fundamental in the HSC niche.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Italy
Location: Italy
Location: Italy
No related grants have been discovered for Francesco Dazzi.