Mesenchymal stem cells protect against malaria pathogenesis by reprogramming erythropoiesis in the bone marrow

Reva S Thakur,Jyoti Das,Meenu Kalkal,Swati Rani,Vikky Awasthi,Anirban Sanyal,Samit Chatterjee,Mrinalini Tiwari,Veena Pande,Rubika Chauhan

doi:10.1038/s41420-020-00363-2

Abstract

Malaria remains a major public health problem worldwide. The immune mechanisms that mediate protection against malaria are still unclear. Previously, we reported that mesenchymal stem cells (MSCs) play a critical role in host protection against malaria by altering the dynamic balance of T regulatory cells and effector T cells producing inflammatory cytokines. Here, we report that MSCs reprogram haematopoiesis in primary (bone marrow) and secondary (spleen) lymphoid organs to provide host protection against malaria. Adoptive transfer of MSCs from malaria-infected mice to naïve recipient mice that were subsequently infected with malaria parasites dramatically accelerated the formation of colony-forming units-erythroid cells in the bone marrow. Adoptively transferred MSCs also induced expression of the key erythroid cell differentiation factor GATA-1 in the spleen of recipient animals. Interestingly, we further observed a subtle increase in the CD34+ hematopoietic stem and progenitor cells in lymphoid organs, including spleen and lymph nodes. Infusion of MSCs also enhanced T cell proliferation, resulting in increased numbers of both CD4+ and CD8+ T cells in the spleen. MSCs also inhibited the induction of the negative co-stimulatory receptor programmed death-1 by T cells in recipient animals upon infection with malaria parasites. Taken together, our findings suggest that MSCs play a critical role in host protection against malaria infection by modulating erythropoiesis and lymphopoiesis.

Highlights

Mesenchymal stromal cells or mesenchymal stem cells (MSCs) are multipotent cells, first described by Friedenstein and colleagues in the 1970s in bone marrow, that exhibit the capacity to adhere to plastic in culture[1]
We observed that infusion of MSCs dramatically lowered parasite growth (Fig. 1A) and increased survival of the animals (Fig. 1B), whereas MSCs from wild type mice did not show any change in parasitaemia and survival of infected mice, which is in agreement with our previous results[30]
Consistent with the FACS data, we found reduced numbers of CD29positive cells in MSC-infused compared with non-infused cells in the spleen of Balb/c mice

Summary

Introduction

Mesenchymal stromal cells or mesenchymal stem cells (MSCs) are multipotent cells, first described by Friedenstein and colleagues in the 1970s in bone marrow, that exhibit the capacity to adhere to plastic in culture[1]. MSCs have self-renewal and differentiation capacity into tissues of mesodermal origin, and support haematopoiesis through the release of various molecules that play important roles in the migration, homing, self-renewal, proliferation, and differentiation of hematopoietic stem. In certain culture conditions adherent stromal cells can support HSPCs15. MSCs can regulate haematopoiesis by producing various growth factors that are required for proliferation as well as differentiation of HSPCs expressing the CD34 surface marker. CD8+ T cells play a limited role during blood-stage malaria[19], these cells can lyse hepatocytes during the pre-erythrocytic stage of infection[20]. It has been shown that programmed death-1 (PD-1), a member of the CD28 family of co-stimulatory molecules, plays a role in the outcome of malaria pathogenesis. PD-1 is induced in activated T, B and MSCs22–25, and interacts with its ligands programmed death-ligand 1 and 2 (PD-L1 and PD-L2)

Methods

Results

Discussion

Conclusion