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Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)-based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adiposederived MSC-based therapy is unsuitable for modulating the progression of K/BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSC-based therapy. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)- based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adiposederived MSC-based therapy is unsuitable for modulating the progression of K/ BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSCbased therapy. [ABSTRACT FROM AUTHOR]

Ex vivo culture of CD34+ has the potential to provide large numbers of cells for clinical use in autologous and allogeneic transplantation and for experimental research involving genetic manipulation. We evaluated the ex vivo expansion of CD34+ cells obtained from bone marrow (BM) and peripheral blood (PB) of untreated patients with chronic myeloid leukaemia (CML) in chronic phase and compared these results with those obtained from BM from normal volunteers (NBM) and peripheral blood after mobilising chemotherapy from patients with non‐haematological disorders (MPB). Selected CD34+ cells were stimulated with interleukin 1(β), interleukin IL‐3, interleukin IL‐6 and stem cell factor. The proliferation observed in patients with CML was similar to that seen in normal donors. CD34+ cells derived from patients with CML are more differentiated than their normal counterparts, as shown by the coexpression of CD34 and CD33 antigens on day 0 (85.6% for CML‐BM and 76.8% for CML‐PB). The culture conditions allowed a significant expansion of granulocyte‐macrophage colony forming units (CFU‐GM) from NBM (33‐fold increase) and MPB (22‐fold increase), in contrast with CML‐derived BM and PB CD34+ cells (2.3‐fold increase). These results indicate that the optimal time to harvest ex vivo expanded cells is dependent on a critical compromise between cell numbers and successful retention of their repopulating potential. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation is a therapeutic alternative for many chronic myeloid leukaemia (CML) patients ineligible for the only curative treatment of allogeneic bone marrow transplantation. In this study the retroviral transduction of CD34+ progenitor cells isolated from the bone marrow (BM) and peripheral blood (PB) of patients with CML was compared to that of CD34+ cells isolated from the BM and PB of normal individuals and patients with non-haematological malignancies. A highly significant increase in transduction of all cell types was achieved in the presence of the recombinant fibronectin fragment, CH-296 (P < 0.05). In the absence of fibronectin, centrifugation produced a marginal improvement in the transduction of all cell types, which was significant only for CMLBM progenitor cells (P < 0.05). There was no significant additive effect when centrifugation was included in the fibronectin infection protocol. In the presence of CH-296, combinations of three or more cytokines improved transduction for all cell types. The same degree of transduction was observed for both normal and CML cells, irrespective of the variations employed in the infection protocol, suggesting that both leukaemic and non-leukaemic progenitors are equally susceptible to retroviral infection. These results demonstrate that CH-296 has a universal beneficial effect on the transduction of haemopoietic progenitor cells, with clear potential for future clinical trials. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have emerged as a promising treatment for inflammatory diseases. The immunomodulatory effect of MSCs takes place both by direct cell-to-cell contact and by means of soluble factors that leads to an increased accumulation of regulatory immune cells at the sites of inflammation. Similar efficacy of MSCs has been described regardless of the route of administration used, the inflammation conditions and the major histocompatibility complex context. These observations raise the question of whether the migration of the MSCs to the inflamed tissues is a pre-requisite to achieve their beneficial effect. To address this, we examined the biodistribution and the efficacy of intraperitoneal luciferase-expressing human expanded adipose-derived stem cells (Luci-eASCs) in a mouse model of colitis. Luci-eASC-infused mice were stratified according to their response to the Luci-eASC treatment. According to the stratification criteria, there was a tendency to increase the bioluminescence signal in the intestine at the expense of a decrease in the bioluminescence signal in the liver in the “responder” mice. These data thus suggest that the accumulation of the eASCs to the inflamed tissues is beneficial for achieving an optimal modulation of inflammation.