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Downregulation of FOXP1 correlates with tendon stem/progenitor cells aging. Xu Hua,Liu Fan Biochemical and biophysical research communications Aging is known as a major risk factor for tendon disorders whereas the molecular mechanisms of age-related tendon disorders still remains unclear. Since tendon-derived stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and healing, in this study we aimed to investigate the role of Forkhead box P1 (FOXP1) in aged TSPCs, we found that FOXP1 mRNA and protein levels were markedly decreased in the aged TSPCs. Moreover, overexpression of FOXP1 attenuates TSPCs aging, as confirmed by decreased of senescence-associated β-gal staining, as well as the senescence marker, p16. Conversely, FOXP1 depletion by siRNA promoted senescence in young TSPCs. Meanwhile, FOXP1 overexpression also restores the age-associated reduction of self-renewal, migration and differentiation of TSPCs. In addition, FOXP1 overexpression rescued decreased levels of E2F1, pRb and cyclin D1 in aged TSPCs, which suggested that FOXP1 regulates TSPCs aging through cellular senescence. These results indicate that FOXP1 plays a crucial role in TSPCs aging. 10.1016/j.bbrc.2018.08.136
The utilization of decellularized tendon slices to provide an inductive microenvironment for the proliferation and tenogenic differentiation of stem cells. Ning Liang-Ju,Zhang Ya-Jing,Zhang Yi,Qing Quan,Jiang Yan-Lin,Yang Jie-Liang,Luo Jing-Cong,Qin Ting-Wu Biomaterials The extracellular matrix (ECM) microenvironment for the stem cell niches, including but not limited to the biochemical composition, matrix topography, and stiffness, is crucial to stem cell proliferation and differentiation. The purpose of this study was to explore the capacity of the decellularized tendon slices (DTSs) to induce stem cell proliferation and tenogenic differentiation. Rat adult stem cells, including tendon-derived stem cells (TDSCs) and bone marrow-derived stem cells (BMSCs), were identified to have universal stem cell characteristics. The DTSs were found to retain the native tendon ECM microenvironment cues, including the inherent surface topography, well-preserved tendon ECM biochemical composition and similar stiffness to native tendon. When the TDSCs and BMSCs were cultured on the DTSs respectively, the LIVE/DEAD assay, alamarBlue® assay, scanning electron microscopy examination and qRT-PCR analysis demonstrated that the DTSs have the capacity to support these stem cells homogeneous distribution, alignment, significant proliferation and tenogenic differentiation. Taken together, the findings of this study indicate that the DTSs can provide a naturally inductive microenvironment for the proliferation and tenogenic differentiation of TDSCs and BMSCs, supporting the use of decellularized tendon ECM as a promising and valuable approach for tendon repair/reconstruction. 10.1016/j.biomaterials.2015.02.061
High cholesterol inhibits tendon-related gene expressions in tendon-derived stem cells through reactive oxygen species-activated nuclear factor-κB signaling. Li Kaiqun,Deng Ganming,Deng Ye,Chen Siwei,Wu Hangtian,Cheng Caiyu,Zhang Xianrong,Yu Bin,Zhang Kairui Journal of cellular physiology Clinical studies have indicated that increased serum cholesterol levels raised the risk of tendinopathy in hypercholesterolemia, but the effect of cholesterol on tendon-derived stem cells (TDSCs) and its underlying mechanism have not been studied. The purpose of this study is to investigate the association between cholesterol and tendinopathy in vitro and in vivo, and its underlying molecular mechanism as well. In TDSCs, the effect of cholesterol was assessed by quantitative polymerase chain reaction, western blot analysis, and immunofluorescence staining. Intracellular levels of reactive oxygen species (ROS) was detected, using flow cytometry. The link between nuclear factor (NF)-κB signaling and the effect of cholesterol was evaluated using a representative IκB kinase (IKK) inhibitor, BAY 11-7082. In addition, Achilles tendons from apolipoprotein E mice fed with a high-fat diet were histologically assessed using hematoxylin and eosin staining and immunohistochemistry. We found that high cholesterol apparently lowered the expression of tendon cell markers (collagen 1, scleraxis, tenomodulin), and elevated ROS levels via the NF-κB pathway both in vitro and in vivo. The ROS scavenger N-acetylcysteine (NAC) and BAY 11-7082 reversed the inhibiting effect of cholesterol on the tendon-related gene expressions of TDSCs. Moreover, NAC blocked cholesterol-induced phosphorylation of IκBα and p65. Significant histological alternation in vivo was shown in Achilles tendon in the hypercholesterolemic group. These results indicated that high cholesterol may inhibit the tendon-related gene expressions in TDSCs via ROS-activated NF-кB signaling, implying pathogenesis of tendinopathy in hypercholesterolemia and suggesting a new mechanism underlying hypercholesterolemia-induced tendinopathy. 10.1002/jcp.28433
Nanotopographic cues and stiffness control of tendon-derived stem cells from diverse conditions. Kim Sun Jeong,Tatman Philip D,Song Da-Hyun,Gee Albert O,Kim Deok-Ho,Kim Sang Jun International journal of nanomedicine BACKGROUND:Tendon-derived stem cells (TDSCs) are key factors associated with regeneration and healing in tendinopathy. The aim of this study was to investigate the effects of mechanical stiffness and topographic signals on the differentiation of TDSCs depending on age and pathological conditions. MATERIALS AND METHODS:We compared TDSCs extracted from normal tendon tissues with TDSCs from tendinopathic Achilles tendon tissues of Sprague Dawley rats in vitro and TDSCs cultured on nanotopographic cues and substrate stiffness to determine how to control the TDSCs. The tendinopathy model was created using a chemical induction method, and the tendon injury model was created via an injury-and-overuse method. Norland Optical Adhesive 86 (NOA86) substrate with 2.48 GPa stiffness with and without 800 nm-wide nanogrooves and a polyurethane substrate with 800 nm-wide nanogrooves were used. RESULTS:TDSCs from 5-week-old normal tendon showed high expression of type III collagen on the flat NOA86 substrate. In the 15-week normal tendon model, expression of type III collagen was high in TDSCs cultured on the 800 nm NOA86 substrates. However, in the 15-week tendon injury model, expression of type III collagen was similar irrespective of nanotopographic cues or substrate stiffness. The expression of type I collagen was also independent of nanotopographic cues and substrate stiffness in the 15-week normal and tendon injury models. Gene expression of scleraxis was increased in TDSCs cultured on the flat NOA86 substrate in the 5-week normal tendon model (=0.001). In the 15-week normal tendon model, scleraxis was highly expressed in TDSCs cultured on the 800 nm and flat NOA86 substrate (=0.043). However, this gene expression was not significantly different between the substrates in the 5-week tendinopathy and 15-week tendon injury models. CONCLUSION:Development and maturation of tendon are enhanced when TDSCs from normal tendons were cultured on stiff surface, but not when the TDSCs came from pathologic models. Therapeutic applications of TDSCs need to be flexible based on tendon age and tendinopathy. 10.2147/IJN.S181743
Matrix stiffness regulates the differentiation of tendon-derived stem cells through FAK-ERK1/2 activation. Liu Chang,Luo Jing-Wan,Liang Ting,Lin Long-Xiang,Luo Zong-Ping,Zhuang Yong-Qing,Sun Yu-Long Experimental cell research Tendon derived stem cells (TDSCs) were vital in tendon homeostasis. Nevertheless, the regulation of TDSCs differentiation in tendinopathy is unclear. Matrix stiffness modulated stem cells differentiation, and matrix stiffness of tendinopathic tissues decreased significantly. In order to clarify the role of matrix stiffness in TDSCs differentiation, they were cultured on the gelatin hydrogels with the stiffness from 2.34 ± 1.48 kPa to 24.09 ± 14.03 kPa. The effect of matrix stiffness on TDSCs proliferation and differentiation were investigated with CCK8 assay, immunofluorescences, real time PCR and western blot. It was found the proliferation of TDSCs increased and more stress fibers formed with increasing matrix stiffness. The differentiation of TDSCs into tenogenic, chondrogenic, and osteogenic lineages were inhibited on stiff hydrogel evidenced by reduced expression of tenocyte markers THBS4, TNMD, SCX, chondrocyte marker COL2, and osteocyte markers Runx2, Osterix, and ALP. Furthermore, the phosphorylation of FAK and ERK1/2 were enhanced when TDSCs grew on stiff hydrogel. After FAK or ERK1/2 was inhibited, the effect of matrix stiffness on differentiation of TDSCs was inhibited as well. The above results indicated matrix stiffness modulated the proliferation and differentiation of TDSCs, and the regulation effect could correlate to the activation of FAK or ERK1/2. 10.1016/j.yexcr.2018.08.023
Effects of young extracellular matrix on the biological characteristics of aged tendon stem cells. Jiang Dapeng,Xu Bo,Gao Peng Advances in clinical and experimental medicine : official organ Wroclaw Medical University BACKGROUND:Age-related changes in the properties of tendon stem cells (TSCs) may play a role in the progressive degeneration and increased risk of injury to tendon tissue. Recent reports have demonstrated that a decellularized extracellular matrix (DECM) can provide an appropriate niche to maintain the proliferation and differentiation capacity of adult stem cells. OBJECTIVES:We investigated the biological effects of DECM obtained from young TSCs on the proliferation, stemness, senescence, and differentiation of the aged TSCs. MATERIAL AND METHODS:Tendon stem cells were isolated from rat patellar tendons and the DECM was collected. The proliferative capacity, β-galactosidase activity, stem cell marker expression, and tenogenic differentiation potential of TSCs were assessed. RESULTS:Our results showed that DECM from young TSCs enhanced the proliferation and tenogenic differentiation of aged TSCs. Moreover, the senescence-associated β-galactosidase activity of aged TSCs was decreased by young DECM. After being cultured on the young DECM, the expression of stem cell markers by aged TSCs was more extensive. The young DECM preserved stem cell properties of aged TSCs. CONCLUSIONS:Taken together, the impaired capacity of aged TSCs can be rejuvenated by exposure to young DECM. The positive results in our study suggest that young TSC-derived DECM may provide a novel approach for the prevention and treatment of age-dependent tendon disorders. 10.17219/acem/75503