Inhibition of JAK-STAT Signaling Pathway Alleviates Age-Related Phenotypes in Tendon Stem/Progenitor Cells

Chen, Minhao; Xiao, Longfei; Dai, Guang-Chun; Lu, Panpan; Zhang, Yuanwei; Li, Yingjuan; Ni, Ming; Rui, Yun Feng

doi:10.3389/fcell.2021.650250

Cited by 22 publications

(17 citation statements)

References 51 publications

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“…During hypothyroidism, STAT5A/B is reduced in lactating rat mammary gland models, while the Janus kinase (JAK) 1 and 2/STAT3 pathway is already known to be involved in thyrotropin (TSH) signaling transduction [ 23 , 24 ]. However, JAK/STAT signaling activation is mainly regulated by a fine-tuned balanced between pro- and anti-inflammatory cytokines present in the microenvironment; impairment in reparative inflammatory cytokine responses is related to maladaptive tendon repair [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Stem Cells from Healthy and Tendinopathic Human Tendons: Morphology, Collagen and Cytokines Expression and Their Response to T3 Thyroid Hormone

Ciardulli

Scala

Giudice

et al. 2022

Cells

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The aim of this study was to investigate the effect of triiodothyronine (T3) on tendon specific markers and cytokines expression of stem cells extracted from human tendons. Indeed, thyroid hormones have been reported to be protective factors, maintaining tendons’ homeostasis, whereas tendinopathy is believed to be related to a failed healing response. Healthy and tendinopathic human tendons were harvested to isolate tendon stem/progenitor cells (TSPCs). TSPCs obtained from pathological samples showed gene expression and morphological modifications at baseline in comparison with cells harvested from healthy tissues. When cells were maintained in a medium supplemented with T3 (10−6 M), only pathological populations showed a significant upregulation of tenogenic markers (DCN, TNC, COL1A1, COL3A1). Immunostaining revealed that healthy cells constantly released type I collagen, typical of tendon matrix, whereas pathological ones overexpressed and secreted type III collagen, typical of scarred and impaired tissue. Pathological cells also overexpressed pro- and anti-inflammatory cytokines, suggesting an impaired balance in the presence of T3, without STAT3 activation. Moreover, DKK-1 was significantly high in the culture medium of pathological cell cultures and was reversed by T3. This study opens perspectives on the complex biochemical alteration of cells from pathological tendons, which may lead to the chronic disease context with an impaired extracellular matrix.

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Section: Introductionmentioning

confidence: 99%

Stem Cells from Healthy and Tendinopathic Human Tendons: Morphology, Collagen and Cytokines Expression and Their Response to T3 Thyroid Hormone

Ciardulli

Scala

Giudice

et al. 2022

Cells

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“… 76 Similarly, a recent study demonstrated that a higher number of senescent cells can be isolated from aged rat ATs. 110 Senescence was associated in aged tenocytes with the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway ( Figure 3 ). Inhibition of this pathway reduced cellular senescence and SASP, as shown by reduced expression of inflammatory and catabolic mediators including IL-6, IL-1β, MMP-3, MMP-9, and CXCL12, thereby restoring the cell function.…”

Section: Pathophysiology Of Tendon Tissue and Cells Affecting At Repairmentioning

confidence: 99%

Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon

Schulze‐Tanzil

Caceres

Stange

et al. 2022

Bone & Joint Research

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Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors. Cite this article: Bone Joint Res 2022;11(8):561–574.

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“…In senescent cells, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway activity is enhanced. Several studies have shown that JAK inhibitors exert anti-aging functions through the JAK/STAT signaling pathway by regulating various cytokines, including SASP [ 136 , 137 , 138 ]. Ruxolitinib is a selective JAK1/2 inhibitor that was originally approved by the FDA for the treatment of myelofibrosis and polycythemia vera [ 139 , 140 ].…”

Section: Antioxidant- and Anti-aging-based Therapeutic Perspectivesmentioning

confidence: 99%

Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies

Wei

Giunta²,

Xia

2022

IJMS

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As the global aging process continues to lengthen, aging-related diseases (e.g., chronic obstructive pulmonary disease (COPD), heart failure) continue to plague the elderly population. Aging is a complex biological process involving multiple tissues and organs and is involved in the development and progression of multiple aging-related diseases. At the same time, some of these aging-related diseases are often accompanied by hypoxia, chronic inflammation, oxidative stress, and the increased secretion of the senescence-associated secretory phenotype (SASP). Hypoxia seems to play an important role in the process of inflammation and aging, but is often neglected in advanced clinical research studies. Therefore, we have attempted to elucidate the role played by different degrees and types of hypoxia in aging and aging-related diseases and their possible pathways, and propose rational treatment options based on such mechanisms for reference.

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Inhibition of JAK-STAT Signaling Pathway Alleviates Age-Related Phenotypes in Tendon Stem/Progenitor Cells

Cited by 22 publications

References 51 publications

Stem Cells from Healthy and Tendinopathic Human Tendons: Morphology, Collagen and Cytokines Expression and Their Response to T3 Thyroid Hormone

Stem Cells from Healthy and Tendinopathic Human Tendons: Morphology, Collagen and Cytokines Expression and Their Response to T3 Thyroid Hormone

Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon

Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies

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