Bone Microvasculature: Stimulus for Tissue Function and Regeneration

Abstract

Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis. Loss or impairment of vascular function can develop diseases, such as large bone defects, avascular necrosis, osteoporosis, osteoarthritis, and osteopetrosis. In this review, we summarize how vasculature controls bone development and homeostasis in normal and disease cases. A better understanding of this process will facilitate the development of novel disease treatments that promote bone regeneration and remodeling. Specifically, approaches based on tissue engineering components, such as stem cells and growth factors, have demonstrated the capacity to induce bone microvasculature regeneration and mineralization. This knowledge will have relevant clinical implications for the treatment of bone disorders by developing novel pharmaceutical approaches and bone grafts. Finally, the tissue engineering approaches incorporating vascular components may widely be applied to treat other organ diseases by enhancing their regeneration capacity. Impact statement Bone vasculature is imperative in the process of bone development, regeneration, and remodeling. Alterations or disruption of the bone vasculature leads to loss of bone homeostasis and the development of bone diseases. In this study, we review the role of vasculature on bone diseases and how vascular tissue engineering strategies, with a detailed emphasis on the role of stem cells and growth factors, will contribute to bone therapeutics.

Keywords: angiogenesis; bone vasculature; diseases; growth factors; osteogenesis; stem cells; tissue engineering.

FIG. 1.

Schematic of bone vasculature. (A) Longitudinal section shows vascular system in the epiphysis, metaphysis, and diaphysis areas of long bone. Boxed regions are magnified in (B). (B) Diagram shows arrangement of arteries and veins, and the blood supply into bone, demonstrating the connection between cortical and medullary blood flow. Periosteal arteries are connected intermittently with cortical blood vessels. Color images are available online.

FIG. 2.

An illustration of the role of microvasculature in bone development. MSCs aggregate and differentiate into chondrocytes to form a cartilage at ∼E13. The hypertrophic chondrocytes in the POC serve as template and stimulate angiogenesis at ∼E15. Blood vessels extend toward the epiphysis at P1 and subsequently invade into them to form the SOCs at P6. Bone development and blood vessel formation are built at P21. MSCs, mesenchymal stromal cells; OBs, osteoblasts; POC, primary ossification center; SOCs, secondary ossification centers. Color images are available online.

FIG. 3.

Schematic for different cell types involved in bone regeneration. Bone and vascular cells are differentiated from MSC types, such as bone marrow (BM-MSCs), adipose (ADSCs), umbilical cord (UCMSCs), urine (USCs), periosteum (PDPCs), induced pluripotent stem cells (iPSC-MSCs), and EPCs, respectively. Macrophages, neutrophils, and monocytes are implicated in the process. BM-MSCs, bone marrow-derived mesenchymal stromal cells; ADSCs, adipose-derived stromal cells; UCMSCs, umbilical cord blood-derived mesenchymal stromal cells; USCs, urine-derived stromal cells; PDPCs, periosteum-derived progenitor cells; iPSC-MSCs, induced pluripotent stem cell-derived mesenchymal stromal cells; EPCs, endothelial progenitor cells. Color images are available online.