Effect of Mesenchymal Stem Cells on the Viability, Proliferation and Differentiation of B Lymphocytes.

Abstract

Mesenchymal stem cells (MSC) are multilineage non hematopoietic progenitor cells that play a key role in supporting the lymphohematopoietic system. Their distribution in bone marrow and secondary lymphoid organs allows an intimate interaction with T and B-lymphocytes, which contribute to the normal lymph node development, but this interaction, can not be considered as a simple bi-directional cross-talk and other cell subsets, such as dendritic cells (DC), must be considered. We have analysed the effect of MSC on B-lymphocytes and the pathways involved in these effects. For these propose, we cultured B-cell with or without MSC and analysed different markers involved in the differentiation of B-cells. We found that MSC inhibited proliferation, arresting B lymphocytes in G0G1 phase of cell cycle (figure 1). However, the presence of MSC increased the viability ob B-lymphocytes (double number of viable B-cells: from 13012 to 22835 Annexin-V PE/7 ADD negative events within B-lymphocytes in absence versus presence of MSC). The exposure of B-cells to plasmocytoid DC (pDC) induced B-lymphocytes differentiation increasing both the percentage of CD38++/CD138++ cells as well as the mean fluorescence intensity of both markers (figure 2). Accordingly, different B-cell subpopulations could be identified which represented a continuum in B-cell maturation. While the levels of cytoplasmic immunoglobulin (cIg) were higher among CD38++ cells, the opposite occurred for the expression of surface Ig as well as CD19 and CCR7. Interestingly, the presence of MSC blocked B-cell differentiation. Regarding the pathways involved in these effects, the presence of MSC influenced on ERK 1/2 and p38 pathways, but these effects depended on the culture conditions. Thus, MSC induced phosphorilation of ERK 1/2 MAPK and inhibited phosphorilation of p38 in B-cells cultured with Ig plus CpG (low proliferative conditions) while the contrary occurred in B-cells cultured with TPA (highly proliferative conditions). Therefore we demonstrated that MSC increased viability and blocked cell cycle of B-lymphocytes. Furthermore the plasmocitoid dendritic cells favoured B-lymphocytes differentiation and this process in inhibited in presence with MSC. These effects are at least in part mediated through the ERK 1/2 and p38 pahtways. Figure Figure

Bone Marrow‐Derived Mesenchymal Stromal Cells Inhibit Th2‐Mediated Allergic Airways Inflammation in Mice

“…Bone marrow‐derived MSCs (BMSCs) have been best characterized and have been found to have significant immunomodulatory and nonimmunogenic properties, allowing administration of allogeneic BMSCs without eliciting an immunogenic response within the host [3–5]. BMSCs inhibit the proliferation and function of a broad range of immune cells in vitro, including T‐cells, B‐cells, natural killer cells, and dendritic cells [6–19]. Notably, BMSCs can suppress CD4 T lymphocyte responses in vitro by inhibiting T‐cell proliferation induced by mitogens or specific antigens [20–31].…”

Immunomodulatory effect of mesenchymal stem cells

“…In our experience MSC promote B-lymphocyte survival while, under highly proliferative conditions, they arrest the B-cell cycle, inhibiting differentiation of B cells into plasma cells (30).…”

“…With regard to cell survival and proliferation, under conditions of low B-cell proliferation we observed that MSC increased ERK1/2 and inhibited p38 MAPK phosphorylation, which may explain the increased viability of B cells in the presence of MSC. Surprisingly, the opposite effect was observed under culture conditions, which favored B-cell proliferation, so that MSC inhibited ERK1/2 phosphorylation and induced activation of p38 MAPK in B cells (30).…”

Heterogeneity of mesenchymal stromal cells in lymphoproliferative disorders

“…Nevertheless, in spite of the reported absence of stromal cytogenetic alterations, even not without controversies, a possible pathogenetic/pathophysiologic role for BM-MSC has been suggested in HM diseases. Although the genetic events are considered primarily responsible for the first step of neoplastic transformation, the development and progression for example of the CLL clone are thought to be affected by various microenvironment signals that regulate proliferation and survival of malignant B cells (75,76). Emerging data on composition of BM microenvironment, especially in CLL, constitute the best in vitro and in vivo model studied.…”

“…B-CLL chemo-resistance involves innate and acquired leukemic side population (94) and the related mechanisms should be better clarified. Indeed, it has been described that MSC seem to increase B-cell viability, while inhibiting proliferation, arresting Blymphocytes in G0/G1 (76). Moreover, it has been observed that stromal cell-mediated notch-1, notch-2 and notch-4 signaling has a role in CLL survival and resistance to chemotherapy.…”