Closed circulatory systems underlie the function of vertebrate organs, but in long bones their structure is unclear although they constitute the exit route for bone marrow (BM) leukocytes. To understand neutrophil migration from BM, we studied the vascular system of murine long bones. Here, in a mouse model, we show that hundreds of capillaries originate in BM, traverse cortical bone perpendicularly along the shaft and connect to the periosteal circulation. Structures similar to these trans-cortical vessels (TCVs) also exist in human limb bones. TCVs express arterial or venous markers and transport neutrophils. Furthermore, over 80% of arterial and 59% of venous blood passes through TCVs. Genetic and drug-mediated modulation of osteoclast count and activity leads to substantial changes in TCV numbers. In a murine model of chronic arthritic bone inflammation, new TCVs develop within weeks. Our data indicate that TCVs are a central component of the closed circulatory system in long bones and may represent an important route for immune cell export from BM.
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We thank the IMaging Center ESsen (IMCES: https://imces.uk-essen.de) Light Microscopy Unit (LMU), the IMCES Electron Microscopy Unit (EMU) and the Optical Imaging Centre Erlangen (OICE: http://www.oice.uni-erlangen.de) for support with imaging. In addition, we wish to thank R. Burgemeister (Carl Zeiss Microscopy) for support through the Zeiss labs@location program and M. Löffler (DCN, TU Dresden) for his help with X-ray microscopy. J. Kamradt is acknowledged for critical reading of the manuscript. This work was supported by funds from the German Research Foundation (SPP1480 Immunobone ) to M.G., G.S., T.K., A.I.G., A.V., G.K. and M.H.; FZT 111 (Center for Regenerative Therapies Dresden, Cluster of Excellence) to A.I.G.; the Collaborative Research Centre (CRC) 1181 to G.K., M.H. and G.S.; the German Ministry of Education and Research (BMBF NeuroImpa 01EC1403A) to T.K.; and the European Union (EU HEALTH-2013-INNOVATION-1, MATHIAS) to M.G.. The work of G.S. was also supported by the Innovative Medicine Initiative (IMI)-funded project RTCure and the European Research Council (ERC) Synergy grant NanoScope.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–9 and Supplementary Tables 1–5
X-ray microscopy (XRM) imaging of a C57BL/6J tibia. X-ray microscopy allows visualization of the compact bone structures of a C57BL/6J tibia, including multiple pores on the bone surface. Optical sectioning of the 3D reconstruction identifies bone pores as canals, traversing the entire compact bone. Zooming into the 3D reconstruction allows the differentiation of bone canals from osteocyte lacunae in the compact bone. Experiments were performed three times individually, with similar results
XRM imaging of C57BL/6J bone canals. Multiple pores can be detected on the surface of a tibia via XRM. While one dominant pore is observed in the posterior metaphyseal bone, numerous smaller pores can be observed all over the bone surface. These pores form canals traversing the entire compact bone. This allows a connection between the bone surface and bone marrow lacuna, shown via an optical journeythrough one exemplary canal. Experiments were performed three times individually, with similar results
LSFM of a simpleClear-treated C57BL/6J tibia. LSFM of a simpleClear optically cleared tibia allows visualization of the entire bone. While there are multiple blood vessels (CD31, red) detected on the bone surface (autofluorescence, grey) forming the periosteum, one dominant vessel is found at the posterior diaphysis. This vessel is entering the bone shaft and ramifies in the bone marrow. Additionally, a central vessel canal can be observed in the centre of the bone marrow, as well as multiple trans-cortical vessels connecting the bone marrow with the bone surface by traversing the compact bone. Experiments were performed six times individually, with similar results
LSFM visualization of a nutrient artery and nutrient sinus. Double staining of CD31 and SCA-1 allows the identification of veins (CD31+SCA-1–, blue) and arteries (CD31+SCA-1+, red) in a simpleClear-treated C57BL/6J tibia. The dominant vessel at the posterior diaphysis shown in Supplementary Video 3 is thereby identified as a nutrient artery, which ramifies in the marrow. The central sinus is exiting the bone shaft (autofluorescence, grey) at the anterior diaphysis. Experiments were performed 15 times individually, with similar results
The periosteal vessel network of a C57BL/6J tibia. High-magnification TPLSM of a simpleClear-treated tibia allows visualization of the arterial (CD31+SCA-1+, red) and venous (CD31+SCA-1–, blue) vessel network in the tissue surrounding the compact bone (SHG, grey). According to their structural orientation, the muscle vascularization can be distinguished from the periosteum, forming a dense vessel network along the bone surface. Experiments were performed five times individually, with similar results
Visualization of arterial and venous connections in a C57BL/6J fibula. High-magnification TPLSM of a fibula showing venous (CD31+SCA-1–, blue) and arterial (CD31+SCA-1+) vessels within the simpleClear-treated bone (SHG, grey). Multiple venous and arterial TCVs are connecting the periosteum to the marrow vascularization within the fibula. In the marrow, the venous central sinus is connected to the sinusoidal network. Additionally, arteries are running along the bone shaft and connected to the sinusoids. Experiments were performed five times individually, with similar results
Blood flow in different cortical vessels. The blood flow in different types of cortical vessel is visualized by intra-vital TPLSM of LysM-EGFP tibiae (SHG, grey). TCVs, nutrient arteries (NAs) and the bone-exiting sinus differ not only in diameter but also in speed of blood flow (rhodamine dextran, red) and cell transport (EGFP, green) (n = 25 TCV, 7 NA and 5 central sinus scans)
Intra-vital imaging of G-CSF mobilization in a LysM-EGFP mouse. Intra-vital imaging of the tibial surface (SHG, grey) shows blood flow (rhodamine dextran, red), but only rarely cell transport (EGFP, green), through TCVs under untreated conditions. About 20 min after application of G-CSF, an increase in cell transport by the bloodstream, as well as active cell migration against the direction of blood flow, can be observed in TCVs and a nutrient artery. Experiments were performed five times individually, with similar results
Location of osteoclasts at the endosteum and in trans-cortical canals. LSFM imaging of a simpleClear-treated CX3CR1-cre;tdTomato tibia shows high numbers of osteoclasts (red) located along the endosteum of the diaphysis. Furthermore, osteoclasts can be found in the vascularized (CD31, turquoise) trans-cortical canals (TCCs) preferentially located in the centre of the compact bone (autofluorescence, grey). Widening of TCCs at these locations may indicate bone remodelling and formation of new TCVs emanating from existing TCCs. Experiments were performed eight times individually, with similar results
Osteoclasts remodelling trans-cortical canals. The generation of SHG signals (grey) via TPLSM imaging enables the visualization of compact bone tissue. The widened TCC area associated with osteoclast location (CX3CR1-cre;tdTomato, red) lacks SHG signals, suggesting the formation of a resorption lacuna where the compact bone tissue is dissolved by the adjacent osteoclast. Experiments were performed three times individually, with similar results
7T MRI imaging of a human shank. 3D reconstruction of 7T MRT data allows visualization of a human shank and identification of specific structures including muscle tissue (brown), compact bone (grey), arteries (red) and veins (blue). Optical clipping of the tibia shows a nutrient artery entering the bone shaft and a central sinus running parallel in the bone cavity. Experiments were performed twice individually, with similar results
Blood flow egression from human bone. Surgical exposure of the human femoral neck shows blood egression from multiple pores on the bone surface. Experiments were performed twice individually, with similar results
Whole-mount-stained and simpleCLEAR-cleared human femoral neck. Whole-mount staining of a human femoral neck with CD31 (turquoise) and α-smooth muscle actin (α-SMA, red) permits visualization of arterial and venous vessels in the human tissue sample. A large artery entering the compact bone (autofluorescence, grey) from the periosteum and a small artery traversing trabeculae in the bone marrow can be observed. Experiments were performed three times individually, with similar results
TCVs in the human femoral neck. Staining of veins (CD31+SCA-1–, turquoise) and arteries (CD31+SCA-1+, red) in the human femoral neck enables visualization not only of the Haversian vascular system in compact bone (autofluorescence, grey), but also of the presence of dTCVs directly connecting the bone marrow with the periosteal vessel network. Experiments were performed four times individually, with similar results
Osteoclast–osteocyte interaction in TCVs. 3D rendering of a confocal scanned histological bone section shows an osteocyte in the compact bone, identified by its characteristic dendritic-like morphology (phalloidin, green, DAPI blue). The osteocyte dendrites are connected to an osteoclast (Cx3cr1-cre;tdTomato, red) located in a TCV (phalloidin, green). Experiments were performed six times individually, with similar results
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Grüneboom, A., Hawwari, I., Weidner, D. et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat Metab 1, 236–250 (2019). https://doi.org/10.1038/s42255-018-0016-5
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