Lymphatic vessels in bone support regeneration after injury

Biswas, Lincoln; Chen, Junyu; Angelis, Jessica De; Singh, Amit; Owen-Woods, Charlotte; Ding, Zhangfan; Pujol, Joan Mane; Kumar, Naveen; Zeng, Fanxin; Ramasamy, Saravana K.; Kusumbe, Anjali P.

doi:10.1016/j.cell.2022.12.031

Cited by 75 publications

(61 citation statements)

References 81 publications

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“…Recently, the Kusumbe lab exploited cutting-edge 3D tissue imaging techniques to dissect blood and lymphatic vessel changes in single-cell resolution to uncover the interactions between vascular and immune cells over time and across different tissues and organs, in which they proposed that the age-dependent vascular and perivascular changes are caused by endothelial cell inflammation and a variety of genes and signals that eventually lead to vascular loss and fibroblast accumulation (Chen et al, 2021). Later, they reported that genotoxic stress-induced IL-6 drives the expansion of lymphatic vessels (lymphangiogenesis) in bone and causes the proliferating lymphatic endothelial cells to secrete CXCL12 to trigger the expansion of Myh11 + CXCR4 + Frontiers in Cell and Developmental Biology frontiersin.org pericytes, which contribute to bone and hematopoietic regeneration (Biswas et al, 2023). These studies shed light on the research of agerelated vascular and bone diseases in the future and may help us to unveil the molecular mechanisms behind the efficacy of KPs and to identify the potential bioactive peptide candidates in preventing VC and osteoporosis simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Kefir peptides attenuate atherosclerotic vascular calcification and osteoporosis in atherogenic diet-fed ApoE−/− knockout mice

Chang

Cheng

Fan

et al. 2023

Front. Cell Dev. Biol.

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Aims: Vascular calcification (VC) and osteoporosis were previously considered two distinct diseases. However, current understanding indicates that they share common pathogenetic mechanisms. The available medicines for treating VC and osteoporosis are limited. We previously demonstrated that kefir peptides (KPs) alleviated atherosclerosis in high-fat diet (HFD)-induced apolipoprotein E knockout (ApoE−/−) mice. The present study further addressed the preventive effects of KPs on VC and osteoporosis in ApoE−/− mice fed a high-cholesterol atherogenic diet (AD).Main methods: Seven-week-old ApoE−/− and wild-type C57BL/6 mice were randomly divided into five groups (n = 6). The development of VC and osteoporosis was evaluated after AD feeding for 13 weeks in KP-treated ApoE−/− mice and compared to C57BL/6 and ApoE−/− mice fed a standard chow diet (CD).Key findings: The results indicated that KP-treated ApoE−/− mice exhibited lower serum total cholesterol, oxidized low-density lipoprotein (ox-LDL), malondialdehyde (MDA) levels, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine kinase (CK) activities, which suggested that KPs prevented hyperlipidemia and possible damages to the liver and muscle in ApoE−/− mice. KPs reduced serum tumor necrosis factor-α (TNF-α) and the local expression of TNF-α, IL-1β, and macrophage-specific CD68 markers in aortic tissues, which suggested that KPs inhibited inflammatory responses in AD-fed ApoE−/− mice. KPs reduced the deposition of lipid, collagen, and calcium minerals in the aortic roots of AD-fed ApoE−/− mice, which suggested that KPs inhibited the calcific progression of atherosclerotic plaques. KPs exerted osteoprotective effects in AD-fed ApoE−/− mice, which was evidenced by lower levels of the bone resorption marker CTX-1 and higher levels of the bone formation marker P1NP. KPs improved cortical bone mineral density and bone volume and reduced trabecular bone loss in femurs.Significance: The present data suggested that KPs attenuated VC and osteoporosis by reducing oxidative stress and inflammatory responses in AD-fed ApoE−/− mice. Our findings contribute to the application of KPs as preventive medicines for the treatment of hyperlipidemia-induced vascular and bone degeneration.

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Section: Discussionmentioning

confidence: 99%

Kefir peptides attenuate atherosclerotic vascular calcification and osteoporosis in atherogenic diet-fed ApoE−/− knockout mice

Chang

Cheng

Fan

et al. 2023

Front. Cell Dev. Biol.

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“…The continuous emerging of clearing tissue protocols in combination with the use of 3D imaging from intact tissues with cell-specific markers is revolutionizing the identification of lymphatic vasculature in tissues that were long considered devoid of them, including the brain and spinal cord in the CNS, the eye, and the bone. The most recent example was the sighting of lymphatic vessels inside the bone in mice and humans (Biswas et al, 2023). However, in the CNS, despite the finding of lymphatic vessels and non-lumenized LECs in the meningeal layers surrounding the surface of the brain (dura mater and leptomeninges, respectively), there is no evidence of the presence of classical lymphatic vasculature inside the brain parenchyma in mammals under physiological conditions.…”

Section: Potential Mechanisms Of Cns Lymphatic Avascularitymentioning

confidence: 99%

“…Due to its relevant role to maintain tissue homeostasis and immune surveillance, lymphatic vasculature is typically found in most of the vascularized tissues, with the notable exception of the bone marrow, cartilage, and the central nervous system (CNS): we should note that, although it was believed that the bone and bone marrow lack lymphatic vessels, very recent work has revealed the presence of lymphatic vessels in bone, supporting bone and hematopoietic cell regeneration (Biswas et al, 2023). The lack of classical lymphatic network in the brain and spinal cord parenchyma limiting the ability to induce an immune OPEN ACCESS EDITED BY Tsutomu Kume, Northwestern University, United States response to CNS-derived antigens was the main reason why the CNS has been considered an immune-privileged organ (Shirai, 1921;Murphy and Sturm, 1923;Medawar, 1948).…”

Section: Introductionmentioning

confidence: 99%

Lymphatic vasculature in the central nervous system

González-Hernández

Mukouyama

2023

Front. Cell Dev. Biol.

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The central nervous system (CNS) is considered as an immune privilege organ, based on experiments in the mid 20th century showing that the brain fails to mount an efficient immune response against an allogeneic graft. This suggests that in addition to the presence of the blood-brain barrier (BBB), the apparent absence of classical lymphatic vasculature in the CNS parenchyma limits the capacity for an immune response. Although this view is partially overturned by the recent discovery of the lymphatic-like hybrid vessels in the Schlemm’s canal in the eye and the lymphatic vasculature in the outmost layer of the meninges, the existence of lymphatic vessels in the CNS parenchyma has not been reported. Two potential mechanisms by which lymphatic vasculature may arise in the organs are: 1) sprouting and invasion of lymphatic vessels from the surrounding tissues into the parenchyma and 2) differentiation of blood endothelial cells into lymphatic endothelial cells in the parenchyma. Considering these mechanisms, we here discuss what causes the dearth of lymphatic vessels specifically in the CNS parenchyma.

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“…It has been suspected for a long time that bone contains lymphatic vessels, but definitive evidence has been lacking ( 29 ). A recent study provided direct evidence for lymphatic vessels ( 30 ). The vasculature also plays a key role in regulating bone homeostasis ( 31 , 32 ).…”

Section: Clinical Implications and Future Directionsmentioning

confidence: 99%