Stem cells are characterized by their capacity to generate multiple cell types, including stem cells with equivalent potential (which has been called self-renewal). These properties, which allow stem cells to participate in organ development and turnover, are preserved and regulated by a specific microenvironment, referred to as a niche. Therefore, the stem cell niche regulates the self-renewal, proliferation, differentiation, and migration of stem cells.
Our lab is interested in the physiological mechanisms by which the microenvironment regulates stem cell function coordinately with the whole organism's demands. We are particularly interested in multisystem regulatory processes that, when deregulated, contribute to disease. These studies will allow for devising more efficient therapeutic approaches that target different components of the stem cell niche.
We mostly use the mouse bone marrow as our model system. Two different stem cell types have been identified in the bone marrow: the hematopoietic stem cell (HSC), which generates all blood and immune cells, and the mesenchymal stem cell (MSC), which produces the stromal cells that form the skeleton and also supports the daily production of blood and immune cells.
HSCs continuously migrate between the bone marrow and the circulation. This physiological traffic can be intensified, allowing for the mobilization and noninvasive harvest of HSCs for life-saving transplantation procedures. The proper engraftment of HSCs in the bone marrow after their infusion is critical for the transplantation's success.
Our recent work has determined that the number of HSCs in the blood is not constant or random but follows circadian oscillations governed by the molecular clock. There are two to three times more HSCs circulating in the blood during the resting period. We took advantage of these oscillations to study the mechanisms regulating physiological HSC traffic. Oscillations in circulating HSCs can be abolished by changes in the light/darkness pattern and mirror fluctuations in the expression of the chemokine CXCL12 in the bone marrow. This chemokine is the only one known to be capable of directing HSC migration.
We have shown that the brain regulates HSC localization and traffic through the sympathetic innervation of the bone marrow, and we have found a new role for the ?3-adrenergic receptor in this process. Norepinephrine release in the bone marrow stem cell niche reduces CXCL12 expression in a particular subset of stromal cells, leading to rhythmic release of HSCs to the bloodstream. Preferential release of HSCs into circulation during the resting period suggests a role in tissue repair. Timing the harvest of HSCs toward their peak release, transplanting them during peak bone marrow homing, or pharmacologically manipulating adrenergic receptors might improve HSC transplantation in patients where it is deemed to be insufficient.
We have identified subendothelial nestin+ cells as the stromal cells that are targeted by the sympathetic nervous system and regulate HSC traffic. These cells have niche properties: they colocalize with HSCs, express high levels of core HSC maintenance genes, selectively down-regulate these genes during HSC mobilization, and their deletion triggers significant alterations in bone marrow HSC homing and content. Subendothelial nestin+ cells are also functional MSCs: 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 highlight the association of MSCs and HSCs in the bone marrow stem cell niche; this association is tightly regulated by local input from the microenvironment and by long-distance cues from hormones and the autonomic nervous system. The findings also present one of the first examples of a somatic stem cell having a niche function for another stem cell.
Elucidation of the functions that self-renewing MSCs have in the HSC niche might facilitate HSC ex vivo expansion for therapeutic purposes. HSC transplantation is routinely performed for lifesaving procedures in patients with hematopoietic malignancies or inherited metabolic/immune disorders. Different HSC sourcessuch as bone marrow, peripheral blood, and cord bloodare used for allogeneic transplantation. The use of cord blood has recently revived because of the scarcity of suitable donors for allogeneic HSC transplantation, its easy and noninvasive harvest, the reduced risk of disease transmission, the immediate availability of cryopreserved units, and the increased tolerance of human leukocyte antigen (HLA) mismatch. However, the limited number of HSCs present in each cord blood has restricted its use to low-body-weight recipients. Ex vivo expansion of cord blood HSCs based on factors produced by self-renewing MSCs would increase the number of patients who would benefit from this therapy.
Our work and that of others points toward a major role for self-renewing MSCs in the integration of neuroendocrine signals that regulate HSC function. Disruption of these regulatory pathways might contribute to the establishment and progression of different diseases. We are investigating neuroendocrine regulatory pathways targeting the bone marrow stem cell niche. This knowledge may contribute to an understanding of how somatic stem cell niches are regulated in the adult mammal to meet physiological demands and may uncover potential therapeutic targets.
Grants from the Spanish Ministries of Education and of Science and Innovation, the American Society of Hematology, and the Marie Curie Actions of the Seventh Framework Program provided partial support for these projects.
As of January 17, 2012