The Hematologist

July-August 2014, Volume 11, Issue 4

Fox Drives CAR Cells in Niche

Mark J. Koury, MD Professor of Medicine, Emeritus
Vanderbilt University School of Medicine, Nashville, TN

Published on: July 17, 2014

Omatsu Y, Seike M, Sugiyama T, et al. Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature. 2014;508:536-540.

Bone marrow hematopoietic niches are highly organized microenvironments that are composed of non-hematopoietic cells and an extracellular matrix that together support the generation and maintenance of vertebrate hematopoietic stem cells (HSCs) and progenitor cells. Areas of the bone marrow that are not involved in hematopoiesis are mainly composed of adipose tissue that serves as an inhibitory microenvironment by restricting hematopoietic progenitor development.1 Marrow hematopoietic niches have osteogenic and endothelial components with interposed cells of various types, including autonomic neurons, glial cells, and macrophages; and, in concert, these elements activate or suppress the function of mesenchymal stem cells (MSCs) and their progeny, specifically chondroblasts, osteoblasts, and adipocytes. Highly specialized subsets of MSCs secrete ligands that bind to surface receptors that mediate induction of quiescence, self-renewal, and differentiation of HSCs, as well as proliferation and differentiation of hematopoietic progenitors. In the bone marrow, these MSC subsets produce the chemokine ligand CXC chemokine ligand-12/stromal cell factor-1 (CXCL12) and the cytokine Kit-ligand/stem cell factor (SCF), which activate their respective receptors, CXCR4 and Kit, on HSCs and hematopoietic progenitors. CXCL12-abundant reticular (CAR) cells comprise one such MSC subset that physically associates with HSCs, produces CXCL12 and SCF, and has both osteogenic and adipogenic differentiation potential.2 Now investigators from the laboratory of Dr. Takashi Nagasawa at the Institute for Frontier Medical Sciences at Kyoto University in Japan, where CAR cells were first identified,3 report that the Forkhead box c1(Foxc1) transcription factor is a key regulator of the hematopoietic niche through its effect on CAR cell function.

In the current study, Dr. Yoshiki Omatsu and colleagues showed that conditional knockout of Foxc1 in all mesenchymal cells of the developing limb led to a marked reduction in CAR cells, HSCs, progenitors of all lineages of hematopoiesis, and circulating blood cells. But while the marrow hematopoietic tissue was found to be reduced in the conditional knockouts, an increase in marrow adipose cells was observed. The residual CAR cells in the marrow were characterized by decreased expression of CXCL12 and SCF with an increased expression of lipid markers and the accumulation of lipid inclusions indicative of differentiation into preadipocytes. Knockout of Foxc1 that was restricted to the majority of CAR cells in young mice was associated with a similar loss of bone marrow CAR and hematopoietic cells with induction of adipocyte development, demonstrating that the phenotype of hematopoietic failure in bone marrow was mainly due to loss of Foxc1 activity in CAR cells. Conversely, in vitro experiments that used forced expression of Foxc1 in marrow-derived preadipocyte cells showed suppression of adipocyte differentiation in conjunction with increased CXCL12 and SCF expression in CAR cells. Inducible knockout of Foxc1 in adult mice caused hematopoietic marrow failure without adipogenesis. Notably, the experimental group was found to have an increase in HSCs and erythropoiesis in the spleen, indicating that extramedullary hematopoiesis was not affected by knockout of Foxc1.

Dr. Omatsu and colleagues demonstrate that Foxc1 expression in bone marrow plays a crucial role in the establishment and maintenance of the hematopoietic niche by orchestrating CAR cell development and CAR cell fate during differentiation while restricting adipocyte development. By fostering the hematopoietic niche in the bone marrow, Foxc1 has actions similar to those of Foxn1, another member of the Fox transcription factor family that is required by thymic epithelium for all T-lymphocyte cell development.4 Understanding how these niche-inducing transcription factors establish and maintain hematopoietic microenvironments has relevance to clinical hematology, where potential manipulation of Foxc1 might be used to treat marrow-based disorders. For example, in normal aging, marrow adipose tissue increases while hematopoietic reserves decrease, resulting in an increased sensitivity to chemotherapy in older adults that limits treatment of malignant diseases. If Fox1c activity could be enhanced in this setting, then increased hematopoietic reserve might improve chemotherapy tolerance and treatment outcomes in older patients. Likewise, enhanced Foxc1 activity has the potential to increase blood cell production in patients with inherited bone marrow failure syndromes, acquired aplastic anemia, and cytopenias after stem cell transplantation. Conversely, decreasing Foxc1 in patients with myeloproliferative disorders may help control excessive hematopoiesis and associated increases in peripheral blood cell counts.

References

  1. Naveiras O, Nardi V, Wenzel PL, et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460:259-263.
  2. Omatsu Y, Sugiyama T, Kohara H, et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity. 2010;33:387-399.
  3. Sugiyama T, Kohara H, Noda M, et al. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977-988.
  4. Nehls M, Kyewski B, Messerle M, et al. Two genetically separable steps in the differentiation of thymic epithelium. Science. 1996;272:886-899.
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