Abstract
Osteoblasts lining the inner surface of bone support hematopoietic stem cell differentiation by virtue of proximity to the bone marrow. The osteoblasts also modify their own differentiation by producing various isoforms of fibronectin (FN). Despite evidence for immune regulation by osteoblasts, there is limited knowledge of how osteoblasts modulate cells of the immune system. Here, we show that extra domain A (EDA)-FN produced by osteoblasts increases arginase production in myeloid-derived cells, and we identify α5β1 as the mediating receptor. In different mouse models of cancer, osteoblasts or EDA-FN was found to up-regulate arginase-1 expression in myeloid-derived cells, resulting in increased cancer growth. This harmful effect can be reduced by interfering with the integrin α5β1 receptor or inhibiting arginase. Conversely, in tissue injury, the expression of arginase-1 is normally beneficial as it dampens the immune response to allow wound healing. We show that EDA-FN protects against excessive fibrotic tissue formation in a liver fibrosis model. Our results establish an immune regulatory function for EDA-FN originating from the osteoblasts and identify new avenues for enhancing the immune reaction against cancer.
Highlights
The inner surface of the bone is lined with preosteoblasts and osteoblasts in the immediate vicinity of bone marrow
Osteoblasts have a close relationship with hematopoiesis, and it has been shown that a transient elimination of osteoblasts leads to the decrease of hematopoietic stem cells and progenitor cells
We analyze the role of FN in hematopoiesis and find that an isoform that contains the extra domain A (EDA) and is produced by the osteoblasts affects both the number and future behavior of a subset of immune cells
Summary
The inner surface of the bone is lined with preosteoblasts and osteoblasts in the immediate vicinity of bone marrow. Several groups have reported a relationship between osteoblasts and hematopoiesis [3,4,5]. These findings culminated in experimental evidence showing that temporary destruction of the osteoblasts led to loss of hematopoietic stem cells as well as various hematopoietic progenitor cells [6]. In line with this, stimulating the osteoblasts with a bone-active hormone called parathyroid hormone led to an increase in myeloid cells in the bone marrow [11]
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