Abstract
The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice.
Highlights
The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown
Here we show that macrophage cells from young animals can rejuvenate fracture repair in old animals
Whereas other studies show that sharing the circulation of a young animal can rejuvenate repair[36,37,38], our data provide evidence that macrophage cells and factors that derive from these cells can rejuvenate repair
Summary
The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Lrp[1] is produced by young cells, and depleting Lrp[1] abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp[1] improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice. Conditioned media experiments show that secreted factors can increase the proportion of cells differentiating to osteoblasts in older animals[9] Whereas this data are consistent with the notion that a secreted factor produced by hematopoietic cells can rejuvenate the pace of fracture repair, neither the hematopoietic cell type, nor the factors are known. Depleting Lrp[1] abrogates the ability to rejuvenate fracture repair, whereas treating old mice with recombinant Lrp[1] improves fracture healing
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