Parenchyma and stroma represent the functional and structural units in every organ of the body
respectively. Stromal cells of mesenchymal origin (MSC) have traditionally been associated with a
structural support activity within the tissue, but it is only recently that more complex functions have
been unveiled. Subsets of MSC have been shown to play a fundamental role in self-renewal and
differentiation of haematopoietic stem cells (HSC). Recent findings show that MSC and bone marrow
(BM) macrophages represent fundamental components in the niche, modulating egress and
mobilization of HSC during normal or emergency myelopoiesis. Therefore, I have decided to
investigate whether and how MSC contribute to the formation and function of myeloid cells. In an in
vitro co-culture model I have observed that MSC have the ability to induce the expansion and
differentiation of different subsets of mature myeloid cells from haematopoietic BM cells. Based on
the differential expression of CD11b and Gr-1, three cell subsets recapitulating myeloid
differentiation could be identified. MSC induced differentiation targets common myeloid progenitors
(CMP) or granulocyte/macrophage progenitors (GMP) but not the primitive HSC. CD11b+ sorted
cells obtained at the end of the co-culture exhibited a functional profile characterised by high levels of
both anti- and pro-inflammatory markers, such as nitric oxide synthase 2 (NOS2) and arginase-1 (ARG-1). In order to identify the mechanisms involved in this phenomenon I have chosen to
investigate a number of molecules involved in the regulation of haematopoietic differentiation by the
microenvironment. I have demonstrated that whilst NOS2 and agrin, an ECM protein, play a key role
in the differentiation of CD11b+ Gr-1- F4/80+ cells, complement appears to be primarily involved in
the generation of CD11b+ Gr-1int-low F4/80- cells. My studies have shown that MSC differentiating
activity is not confined to the BM but can also be detected in MSC from other tissues like skin and
kidney. Overall these results suggest a key role for stromal cells as regulators of myeloid
differentiation. Further investigation is under way to assess the importance of such a function in vivo.