Diversity of Vascular Niches in Bones and Joints During Homeostasis, Ageing, and Diseases

The bones and joints in the skeletal system are composed of diverse cell types, including vascular niches, bone cells, connective tissue cells and mineral deposits and regulate whole-body homeostasis. The capacity of maintaining strength and generation of blood lineages lies within the skeletal system. Bone harbours blood and immune cells and their progenitors, and vascular cells provide several immune cell type niches. Blood vessels in bone are phenotypically and functionally diverse, with distinct capillary subtypes exhibiting striking changes with age. The bone vasculature has a special impact on osteogenesis and haematopoiesis, and dysregulation of the vasculature is associated with diverse blood and bone diseases. Ageing is associated with perturbed haematopoiesis, loss of osteogenesis, increased adipogenesis and diminished immune response and immune cell production. Endothelial and perivascular cells impact immune cell production and play a crucial role during inflammation. Here, we discuss normal and maladapted vascular niches in bone during development, homeostasis, ageing and bone diseases such as rheumatoid arthritis and osteoarthritis. Further, we discuss the role of vascular niches during bone malignancy.

Post-myocardial infarction heart failure dysregulates the bone vascular niche

The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.

Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis

Angiogenesis and osteogenesis are coupled. However, the cellular and molecular regulation of these processes remains to be further investigated. Both tissues have recently been recognized as endocrine organs, which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues. This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature. In addition, research progress related to the bone vasculature, vessel-related skeletal diseases, pathological conditions, and angiogenesis-targeted therapeutic strategies are also summarized. With respect to future perspectives, new techniques such as single-cell sequencing, which can be used to show the cellular diversity and plasticity of both tissues, are facilitating progress in this field. Moreover, extracellular vesicle-mediated nuclear acid communication deserves further investigation. In conclusion, a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.

Mechanisms of bone blood flow regulation in humans

Bone is a highly vascularized tissue. However, despite the importance of appropriate circulationfor bone health, regulation of bone blood flow remains poorly understood. Invasive animalstudies suggest that the sympathetic activity plays an important role in bone flow control.However, it remains unknown if bone vasculature evidences robust vasoconstriction in responseto sympathoexcitatory stimuli. Here, we characterized bone blood flow in young healthyindividuals (N=13,(4F)) in response to isometric handgrip exercise (IHE) and cold pressor test(CPT). These provide a strong stimulus for active vasoconstriction in the inactive muscle, andperhaps also in the bone. During sustained IHE to fatigue and CPT, we measured blood pressure,whole leg blood flow, and tibial perfusion using near-infrared spectroscopy. Tibia perfusion wasdetermined as oxy- and deoxy-hemoglobin. For both stimuli, tibial metabolism remainedconstant (i.e., no change in deoxyhemoglobin) and thus tibial arterial perfusion was representedby oxyhemoglobin. During IHE, oxyhemoglobin declined (beginning -0.20±1.04μM; end -1.13±3.71μM, both p<0.01) slower than whole leg blood flow (beginning -0.85±1.02cm/s; end -2.72±1.64cm/s, both =p<0.01). However, during CPT, both oxyhemoglobin (beginning -0.46 ±1.43μM; end -0.60±1.59μM, both p<0.01) and whole leg blood flow (beginning -1.52±1.63 cm/s;end -0.69±1.51cm/s, both p<0.01) declined with a similar time course, even though themagnitudes of decline were smaller than during IHE. These responses are likely due the differenttime courses of sympathetically mediated vasoconstriction in bone and muscle. These resultsindicate that sympathetic innervation of the bone vasculature serves a functional role in thecontrol of flow in young healthy individuals.

Spatio-Temporal Bone Remodeling after Hematopoietic Stem Cell Transplantation

The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology.

Blood Vessels and Vascular Niches in Bone Development and Physiological Remodeling

Recent advances in our understanding of blood vessels and vascular niches in bone convey their critical importance in regulating bone development and physiology. The contribution of blood vessels in bone functions and remodeling has recently gained enormous interest because of their therapeutic potential. The mammalian skeletal system performs multiple functions in the body to regulate growth, homeostasis and metabolism. Blood vessels provide support to various cell types in bone and maintain functional niches in the bone marrow microenvironment. Heterogeneity within blood vessels and niches indicate the importance of specialized vascular niches in regulating skeletal functions. In this review, we discuss physiology of bone vasculature and their specialized niches for hematopoietic stem cells and mesenchymal progenitor cells. We provide clinical and experimental information available on blood vessels during physiological bone remodeling.