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The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes

Servicio de Hematología, Hospital Clínico Universitario and Centro de Investigación del Cáncer (CIC); Servicio de Citometría, Universidad de Salamanca, Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain

Correspondence: José A. Pérez Simón, Servicio de Hematología, Hospital Clínico Universitario y CIC, Paseo de San Vicente s/n, 37007, Salamanca, Spain. E-mail:pesimo{at}usal.es

Background: Mesenchymal stem cells 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. While their effect on T-lymphocytes has been extensively analyzed, data on the effect of mesenchymal stem cells on B cells are more limited. We analyzed the effects of mesenchymal stem cells on B-lymphocytes and the pathways involved in these effects.

Design and Methods: The effect of MSC on the proliferation and viability of B cells was evaluated using MTT assays, annexin/7-amino-actinomycin D and propidium iodide staining. The B-cell maturation pattern was established using flow cytometry based on the expression of different markers related to the differentiation of B cells, such as CD38, CD138, CD19 and CCR7, and to the expression of surface and intracellular immunoglobulins. Finally, western blot assays were used to identify the pathways involved in the effects of mesenchymal stem cells on B-lymphocytes.

Results: Mesenchymal stem cells increased viability and blocked the cell cycle of B-lymphocytes in the G₀/G₁ phase. In vitro exposure of B cells to plasmacytoid dendritic cells induced B-cell differentiation as shown by an increased number of CD38⁺⁺/CD138⁺⁺ cells, which also displayed higher levels of cytoplasmic immunoglobulin and lower levels of CD19, CCR7 and surface immunoglobulin. Interestingly, this maturation pattern was inhibited by adding mesenchymal stem cells to the culture. Finally, mesenchymal stem cells modified the phosphorylation pattern of the extracellular response kinase 1/2 and p38 pathways which are both involved in B-cell viability, proliferation and activation.

Conclusions: Mesenchymal stem cells increase B-cell viability while inhibiting proliferation, arresting B-lymphocytes in the G₀/G₁ phase of the cell cycle. The presence of mesenchymal stem cells blocked B-cell differentiation as assessed by flow cytometry. Finally, mesenchymal stem cells modified the activation pattern of the extracellular response kinase and the p38 mitogen-activated protein kinase pathways in B-lymphocytes.

Key words: mesenchymal stem cells, B lymphocytes, cell survival, B-cell differentiation.