Adaptive and Innate Immune Cell Responses in Tendons and Lymph Nodes After Tendon Injury and Repair

Abstract

Tendon injuries are a common clinical condition with limited treatment options. The cellular components of the innate system, such as neutrophils and macrophages, have been well studied in tendon injuries. However the adaptive immune system, comprised of specialized lymphocytes, plays an important role in orchestrating the healing of numerous tissues but less is known about these cells in tendon healing. To gain a greater understanding of the biological processes that regulate tendon healing, we sought to determine how the cellular components of the adaptive and innate immune system respond to a tendon injury using two-month old male mice. We determined that the lymphatic vasculature is present in the epitenon and superficial regions of Achilles tendons. We then created an acute Achilles tenotomy followed by repair, and collected tendons and draining lymph nodes one, two, and four weeks after injury. Using flow cytometry and histology, after tendon injury we observed a robust adaptive immune cell response that followed an initial innate immune cell response. There was an accumulation of monocytes, neutrophils, and macrophages one week after injury that declined thereafter. Dendritic cells and CD4 + T cells peaked two weeks after injury, while B cells and CD8 + T cells progressively increased over time. In parallel, immune cells of the draining popliteal lymph node demonstrated a similarly coordinated response to the injury. These results suggest that there is an adaptive immune response to tendon injury and adaptive immune cells may play a role in regulating tendon healing.

Scleraxis is required for the growth of adult tendons in response to mechanical loading

“…In the patellar tendon, approximately 0.8% of cells are CD146 + (18), which is consistent with the relatively low amount of vasculature within homeostatic adult tendon (3). Previous studies in our laboratory using the synergist ablation model in rats showed that these cells appear to migrate from their niche in the vasculature and proliferate within the neotendon (15).…”

“…Tenocytes, or tendon fibroblasts, are the main cell type in tendons and are thought to be responsible for the production, organization, and maintenance of the tendon ECM (2). Tendons are surrounded by an outermost basement membrane called the epitenon, which provides blood and nerve supply to the tendon (1,3). The organization of the ECM allows the tendon to properly transmit forces from muscle to bone and allow for locomotion, and to respond to mechanical stimuli (4,5).…”

Widespread diversity in the transcriptomes of functionally divergent limb tendons

“…Tenocytes, or tendon fibroblasts, are the most abundant cell type in tendon tissue and are responsible for ECM production, hierarchical organization and repair (Gumucio et al 2015). Tendons are also composed of endothelial cells, sensory neurons and tissue resident immune cells, among others, that provide a vascular supply, allow for proper motor control, and support the general growth and homeostatic functions of tendon tissue (Sugg et al 2014;Ackermann et al 2016;Noah et al 2020).…”

Magnetic Stimulation Drives Macrophage Polarization in Cell to–Cell Communication with IL-1β Primed Tendon Cells

“…Biological functions and homeostasis rely on complex cell responses to microenvironmental stimuli. The articulated interplay of immune cells and resident cell population is critical for timely and spatial regulation to achieve proper healing and stimulate regeneration [ 10 ]. Although inflammatory cues are necessary to trigger the repair mechanisms, if perpetuated, pro-inflammatory signals can impair regenerative response and produce a deleterious effect on tendon functionality [ 21 ].…”

“…Although immune cells are necessary for tendon repair, their persistent activation can result in incomplete resolution of inflammation [ 8 ] and may lead to chronic injury [ 9 ]. Recent studies indicated that the adaptive and innate immune systems work with tissue resident cells to coordinate tissue repair [ 10 ], suggesting that the mechanisms to counteract inflammatory stimuli may be insufficient in natural tendon injury. Consequently, this limited intrinsic response creates new opportunities to investigate the interplay of immune cells and human tendon cells (hTDCs) envisioning new molecular and cellular treatment possibilities.…”