By Michael McDevitt, MD, PhD

2008-12-08

The bone marrow is a specialized microenvironment. Conventional histologic and immunohistologic analysis has identified a generally orderly arrangement of developing cells in the bone marrow, including the presence of early granulocytic cells along the bony trabecular margins, erythroid islands, megakaryocytes, and occasional lymphoid nodules positioned in the intertrabecular spaces. Recent technological advances have helped to identify a specialized component of the bone marrow microenvironment, the “niche.” This three-dimensional functional hematopoietic unit has specialized anatomical relationships between bone, blood vessels, and differentiating hematopoietic cells. As such, the hematopoietic stem cell (HSC) niche functions as an anatomically confined regulatory environment governing HSC numbers and fate.

The identity of mesenchymal stem cells (MSCs) and their relationship to HSCs remain poorly defined. In addition, there are discrepancies regarding the cellular constituents of the HSC niche, with studies suggesting a role for bone-lining osteoblasts and other data implicating sinusoidal endothelial and adventitial reticular cells. Following Sunday’s Plenary Session presentation by Dr. Simon Mendez-Ferrer, of Mount Sinai School of Medicine in New York, there is much less uncertainty (abstract #4).

Previous work from this group has demonstrated a role for the sympathetic nervous system (SNS) in HSC mobilization induced by G-CSF (Katayama, et al. 2006; Cell. 124:407-21). A pathway of circadian oscillations is governed by a molecular clock and triggered by cyclical norepinephrine secretion by the SNS in the bone marrow, activation of the b3-adrenergic receptor (encoded in Adrb3), degradation of the Sp1 transcription factor, and down-regulation of Cxcl12 components of this pathway (Mendez-Ferrer, et al. 2008; Nature. 452:442-7).

Now the group has identified the cell targeted by the SNS in the bone marrow as a perivascular stromal cell expressing Nestin, an intermediate filament protein characteristic of neuroectoderm-derived stem cells. In elegant experiments utilizing transgenic mice expressing GFP under the regulatory elements of the Nestin promoter, Dr. Mendez-Ferrer showed that virtually all catecholaminergic fibers in the bone marrow were associated with Nestin+ cells. Further evidence that Nestin-driven GFP-positive cells are part of the pathway included observations of the expected high expression of the chemokine CXCL12 and Adrb3 in these cells. Detailed immunofluorescence analyses of the spatial distribution of HSCs in longitudinal bone marrow sections revealed significant colocalization of HSCs and candidate Nestin+ MSCs in the endosteal or sinusoidal regions of the bone marrow. In long-term bone marrow cultures, Nestin+ cells were rare, but suspiciously located near HSCs/progenitor-enriched cobblestone-forming areas. Additional experiments provided evidence of functional interaction of bone marrow Nestin+ cells and HSCs.

Detailed b adrenergic receptor studies provide convincing evidence for a role of the SNS in regulating HSC adhesion in the bone marrow niche. Ex vivo cell sorting of Nestin+ CD45- and Nestin- CD45- bone marrow cells revealed that all the mesenchymal progenitor activity of the bone marrow (CFU-F) was contained in the Nestin+ cell fraction, and Nestin+ cells could robustly differentiate into osteoblasts and adipocytes. Lineage-tracing studies confirmed the contribution of Nestin+ cells to osteoblasts and chondrocytes during development, and additional long-term colony assays with hematopoietic versus mesenchymal growth factors provided supportive data for the general hypothesis that the HSC niche is composed of a heterotypic MSC−HSC pairing that is tightly regulated by the SNS. The authors suggest that this association may reconcile divergent views regarding the vascular and osteoblastic locations of the HSC niche, and its regulation by the SNS might explain the crosstalk between hematopoietic and mesenchymal lineages in the bone marrow through either health or disease.

Dr. McDevitt indicated no relevant conflicts of interest.

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