Mammal comparative tendon biology: advances in regulatory mechanisms through a computational modeling

Abstract

There is high clinical demand for the resolution of tendinopathies, which affect mainly adult individuals and animals. Tendon damage resolution during the adult lifetime is not as effective as in earlier stages where complete restoration of tendon structure and property occurs. However, the molecular mechanisms underlying tendon regeneration remain unknown, limiting the development of targeted therapies. The research aim was to draw a comparative map of molecules that control tenogenesis and to exploit systems biology to model their signaling cascades and physiological paths. Using current literature data on molecular interactions in early tendon development, species-specific data collections were created. Then, computational analysis was used to construct Tendon NETworks in which information flow and molecular links were traced, prioritized, and enriched. Species-specific Tendon NETworks generated a data-driven computational framework based on three operative levels and a stage-dependent set of molecules and interactions (embryo–fetal or prepubertal) responsible, respectively, for signaling differentiation and morphogenesis, shaping tendon transcriptional program and downstream modeling of its fibrillogenesis toward a mature tissue. The computational network enrichment unveiled a more complex hierarchical organization of molecule interactions assigning a central role to neuro and endocrine axes which are novel and only partially explored systems for tenogenesis. Overall, this study emphasizes the value of system biology in linking the currently available disjointed molecular data, by establishing the direction and priority of signaling flows. Simultaneously, computational enrichment was critical in revealing new nodes and pathways to watch out for in promoting biomedical advances in tendon healing and developing targeted therapeutic strategies to improve current clinical interventions.

Assessing the functional potential of conditioned media derived from amniotic epithelial stem cells engineered on 3D biomimetic scaffolds: An in vitro model for tendon regeneration

“…RANTES has a role in promoting vascular and neuronal mediators essential for tendon development and healing process [70]. In contrast, Transforming Growth Factor-β (TGF-β), pivotal in tendon healing [ [48] , [49] , [50] , [51] ], exhibited a decreased release within CM 2D and CM 3D with respect to CM CTR . However, TGF-β reduced secretion can be positively considered, since its modulation is necessary to avoid fibrotic scar tissue formation [ 52 , 53 ] and possibly support a correct regenerative process after scaffold transplantation.…”

Unraveling the link: locomotor activity exerts a dual role in predicting Achilles tendon healing and boosting regeneration in mice

“…Mechanical signals, modulated by factors such as SCX, an early marker of tendon development, and TGF, may enhance the transmission of mechanical signals in mice with bilateral tendon injuries and unrestricted wheel activity. This modulation may lead to spatial changes in the actin cytoskeleton of stretched tenocytes, promoting cell alignment and rearrangement and facilitating ECM deposition within the tendon ( 51–53 ). Moreover, SCX plays a crucial role in initiating tendon differentiation, while MKX, a crucial transcription factor for tendon development, is involved in tissue growth and collagen fibril assembly ( 54 ).…”

Growth factors in the treatment of Achilles tendon injury

“…GFs are a class of cytokines secreted by cells and participate in various biological activities by binding to specific, high-affinity receptors to maintain and regulate the growth and metabolism of the body. A study retrieved 2,332 publications on early tendon development, draw a comparative map of molecules that control tenogenesis, and found several hub genes that plays an important role in tendon development, including TGF-βs, BMPs, FGFs, IGFs ( Peserico et al, 2023 ). These GFs related to tenogenesis paths belonging to macro-categories such as (1) growth, differentiation and survival, (2) morphogenesis and cell motility, (3) nervous system, (4) and endocrine system.…”

“…As the upstream molecules of Scx, TGF-β and FGF coordinately induce the development of axial and limb tendon progenitors via Scx action. TGF-β plays a central role in tendon development, and TGFB receptors are expressed in tendon progenitor cells, the genetic deletion of TGFBR2 or TGFB2 results in failure of tendon development ( Peserico et al, 2023 ). TGF-β1, -β2, and -β3 have distinct spatiotemporal developmental protein localization patterns in the developing tendon and may probably have independent roles in tendon development ( Kuo et al, 2008 ).…”