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Stem cell niche pathophysiology

Stem cells reside in specialized niches that allow them to self-renew, proliferate, differentiate and migrate according to the organism’s requirements. Our group studies the mechanisms by which the stem cell niche fulfils these complex functions and how its deregulation contributes to disease.

Our recent work has described a tight regulation of the bone marrow stem cell niche by circadian oscillations of sympathetic activity. Light onset induces noradrenaline release in the bone marrow, leading to rapid downregulation of CXCL12/SDF-1, the only chemokine known to direct haematopoietic stem cell (HSC) migration. Our recent studies indicate that the stromal cells targeted by the sympathetic nervous system that regulate HSC traffic are peri-vascular nestin+ cells. These cells are true niche cells: they colocalize with HSC, express high levels of core HSC maintenance genes, selectively downregulate these genes during HSC mobilisation and their deletion triggers significant alterations in bone marrow HSC homing and content. Interestingly, peri-vascular nestin+ cells are also functional mesenchymal stem cells (MSC): they account for all mesenchymal activity, show clonal multilineage differentiation, display robust self-renewal in serial transplantations and contribute to osteochondral lineages in vivo. These findings suggest that the bone marrow stem cell niche is composed of a unique pairing of MSC and HSC, tightly regulated by local input from the microenvironment and by long-distance cues from hormones and the autonomic nervous system.

We are currently investigating novel physiological mechanisms that regulate the stem cell niche and contribute to pathogenesis, with the ultimate goal of devising more efficient therapeutic approaches targeting the stem cell niche.

Figure 1 Figure 1: Peri-vascular nestin+ mesenchymal stem cells are innervated by sympathetic fibers in the bone marrow. Projection stack (~100 µm) of fluorescent images showing the distribution of Nestin-GFP+ cells (green), CD31/PECAM+ vascular endothelial cells (blue) and tyrosine hydroxylase+ sympathetic nerve fibers (red) after whole mount staining of the skull bone marrow.

Figure 2 Figure 2: A bone marrow stem cell niche made for two. Projection stack (~15 µm) of fluorescent images showing a CD150+ (red) CD48-, CD3e-, Ter119-, Gr1-, B220- and CD11b- (antigens labeled in blue) hematopoietic stem cell adjacent to a nestin-GFP+ mesenchymal stem cell (green) in the bone marrow (from Nature 466: 829-34). Grid, 50 µm.

Simón Méndez Ferrer
  • Méndez Ferrer, Simón
  • Visiting scientist
  • Ext. 3310

Simón Méndez-Ferrer received his BSc in 1998 and his PhD in 2004 from the Universidad de Sevilla. His doctoral work, performed in the Department of Medical Physiology under the direction of José Lopez-Barneo and Juan José Toledo-Aral, characterized properties of the carotid body of potential interest for neuroregenerative strategies based on the biological delivery of catecholamines and neurotrophic factors. His work during his postdoctoral period in the laboratory of Paul S. Frenette at Mount Sinai School of Medicine (New York, 2006-09) showed that hematopoietic stem cell traffic is regulated by circadian oscillations and described the mechanism underlying this. His subsequent work as an Assistant Professor at Mount Sinai (2009-10) used nestin expression as a marker to identify self-renewing mesenchymal stem cells, and determined their crucial role in the hematopoietic stem cell niche. Simón is supported by the Ramón y Cajal Program, and joined the CNIC in late 2010.