MSC-HSC NICHE · Homeostatic regulation of mesenchymal stem cells in the haematopoietic stem-cell niche

The cells forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear. Our recent studies have demonstrated that mesenchymal stem cells (MSC) identified using expression of the intermediate filament protein nestin constitute an essential HSC niche component. Nestin+ cells contribute to bone formation, contain all the mesenchymal activity and can self-renew and expand in serial transplantations. Nestin+ MSC are spatially associated with HSC and fibres from the sympathetic nervous system, and highly express HSC maintenance genes. These genes and others triggering nestin+ MSC differentiation are selectively downregulated during enforced HSC mobilisation or β3-adrenoceptor activation. Parathormone treatment doubles bone marrow nestin+ cells and favours their osteoblastic differentiation. In contrast, in vivo nestin+ MSC depletion rapidly mobilises HSC from the bone marrow to extramedullary sites. Purified HSC rapidly home near nestin+ MSC in the bone marrow of lethally irradiated mice, whereas in vivo nestin+ MSC depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem cell types and argue for a unique niche in the bone marrow. Nestin+ MSC sharing some properties with the ones previously characterised in post-natal bone marrow are present in the foetal liver. In this proposal, we will characterise specific functions nestin+ cells in the adult HSC niche, and will analyse the role of nestin+ MSC during developmental HSC migration. We will also study the homeostatic regulation of the bone marrow stem-cell niche by analysing the role of autonomic and hormonal signals on the proliferation and fate of MSC and HSC. These studies will offer insight into the homeostatic regulation of a somatic stem-cell niche and uncover potential therapeutic targets to stimulate skeletal regeneration and HSC homing, engraftment and mobilisation.