The blood-tendon barrier: identification and characterisation of a novel tissue barrier in tendon blood vessels

Abstract

Tissue barriers function as "gate keepers" between different compartments (usually blood and tissue) and are formed by specialised membrane-associated proteins, localising to the apicolateral plasma membrane domain of epithelial and endothelial cells. By sealing the paracellular space, the free diffusion of solutes and molecules across epithelia and endothelia is impeded. Thereby, tissue barriers contribute to the establishment and maintenance of a distinct internal and external environment, which is crucial during organ development and allows maintenance of an organspecific homeostatic milieu. So far, various epithelial and endothelial tissue barriers have been described, including the blood-brain barrier, the blood-retina barrier, the blood-testis barrier, the blood-placenta barrier, and the cerebrospinal fluid (CSF)-brain barrier, which are vital for physiological function and any disturbance of these barriers can result in severe organ damage or even death. Here, we describe the identification of a novel barrier, located in the vascular bed of tendons, which we term the bloodtendon barrier (BTB). By using immunohistochemistry, transmission electron microscopy, and tracer studies we demonstrate the presence of a functional endothelial barrier within tendons restricting the passage of large blood-borne molecules into the surrounding tendon tissue. We further provide in vitro evidence that the BTB potentially contributes to the creation of a distinct internal tissue environment impacting upon the proliferation and differentiation of tendon-resident cells, effects which might be fundamental for the onset of tendon pathologies.

A high-glucose diet affects Achilles tendon healing in rats

“…qRT-PCR was performed as described in Lehner, et al . 18 , using TaqMan® assays (Integrated DNA Technologies, Coralville, IA, USA) targeting Sox9 (SRY box 9), Col2a1 (collagen, type II, alpha 1), Acan (aggrecan), Comp (cartilage oligomeric matrix protein), Fabp2 (fatty acid binding protein 2), Pparγ (peroxisome proliferator-activated receptor γ), Runx2 (runt-related transcription factor 2), Col1a1 (collagen type 1 α1), Col3a1 (collagen type 3 α1), Scx (scleraxis), Mkx (mohawk), Tnmd (tenomodulin), Il1b (interleukin 1b), Il6 (interleukin 6), Il10 (interleukin 10) (see also SI methods for details).…”

Bevacizumab Improves Achilles Tendon Repair in a Rat Model

“…Interestingly, in healthy tendons blood vessels are relatively tight, establishing a sizeselective interface and restricting the free passage of blood-borne components into the tendon proper [6]. This protection is essential, as we have previously shown that the presence of serum is required for tendon stem/progenitor cell differentiation, particularly towards the osteogenic lineage.…”

“…Moreover, serum contact causes upregulation of the matrix degrading enzymes MMP2 and MMP9. Thus, excessive supply with blood components may contribute to unfavorable processes following tendon injury, such as erroneous cell differentiation, disturbance of matrix organization and concomitant impairment of mechanical function [6].…”

CX3CL1 and CX3CR1 Expressing Tendon Cells – A novel Immune Cell Population in the Tendon Core

“…qRT-PCR was performed as described by Lehner et al using TaqMan ® assays from IDT (Integrated DNA Technologies, Coralville, IA, USA) targeting all genes listed in Table 1 (Lehner et al, 2016). Amplification conditions were 50 °C for 2min, 95 °C for 10min, followed by 40 cycles of 95 °C for 15 s and 60 °C for 1 min.…”

“…As the majority of these cells are usually situated in the vicinity of blood vessels (Hume et al, 1984), it seems plausible that this would also apply for tissue-resident myeloid cells in tendons. However, the presence and distribution of immune cells in healthy tendons has not been thoroughly investigated so far and due to the hypovascular nature of tendons, we hypothesize that in tendons resident myeloid cells not only are present in the perivascular region, but also reside within the dense, collagen-rich tendon core fulfilling a surveillance function similar to Langerhans cells in the skin or microglia in the brain (Deckers et al, 2018; Lehner et al, 2016).…”