Impaired function of tendon-derived stem cells in experimental diabetes mellitus rat tendons: implications for cellular mechanism of diabetic tendon disorder

Shi, Liu; Li, Yingjuan; Dai, Guang-Chun; Li, Gang; Wang, Chen; Chen, Hui; Rui, Yun Feng

doi:10.1186/s13287-018-1108-6

Cited by 19 publications

(31 citation statements)

References 37 publications

(53 reference statements)

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“…The multi-differentiation methods of TSPCs were elaborated in previous studies (Rui et al, 2010;Shi et al, 2019). TSPCs (P3) isolated from ossified tendon were seeded at 4 × 10 3 cells/cm 2 in 12-well plates and cultured in complete medium until confluence.…”

Section: Osteogenic Differentiation Assaymentioning

confidence: 99%

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

Dai

Liu

et al. 2020

Front. Cell Dev. Biol.

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Although the mineralization in tendon tissue has been reported in a series of aging and disease models, the underlying mechanisms remain unknown. This study aimed to describe the appearance of heterotopic ossification in rat Achilles tendon and further verify whether this tissue metaplasia is related to the enhanced osteogenic differentiation of tendon stem/progenitor cells (TSPCs) owing to the higher expression of bone morphogenetic proteins (BMP-2/4/7) with aging. The male SD rats, aged 4, 8, and 20 months (M), were used. The analyses of ossification and BMP expression in tendon were tested by radiological view (X-ray and CT), histological staining [hematoxylin and eosin (HE), Alcian blue, and Alizarin red], immunohistochemistry, and Western blot. The osteogenic differentiation potential and BMP expression of TSPCs were examined by Alizarin red S staining and real-time PCR. TSPCs were treated with BMP-2 or noggin, and the osteogenic differentiation potential was also examined. X-ray and CT showed the appearance of heterotopic ossification in tendon, and the volume and density of ossification was increased with aging. Histological staining showed the appearance of calcified region surrounded by chondrocyte-like cells and the increased osteogenesis-related gene and BMP expression in ossified tendon with aging. Moreover, the osteogenic differentiation potential and BMP expression in TSPCs isolated from ossified tendon were increased with aging. Additionally, BMP-2 increased the calcium nodule formation and osteogenesis-related gene expression in TSPCs. The addition of noggin inhibited BMP-induced enhancement of osteogenic differentiation. Thus, these findings suggested that the enhanced osteogenic differentiation of TSPCs contributes to the increased heterotopic ossification in aged tendon, which might be induced by the higher expression of BMPs with aging.

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Section: Osteogenic Differentiation Assaymentioning

confidence: 99%

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

Dai

Liu

et al. 2020

Front. Cell Dev. Biol.

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“…Diabetes mellitus (DM), as a systemic metabolic disorder, is an important risk factor for the development and poor prognosis of tendinopathy. 5 Advanced glycation end products (AGEs), kinds of oxidative derivatives resulting from diabetic hyperglycaemia, are known to contribute to the complications of DM by raising intracellular oxidative stress. 3 TDSCs can promote tendon repair and regeneration, and maintain tendon homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…4 Impaired function of TDSC may account for the structural alternations in DM tendons, which may exacerbate tendon matrix degradation and tendinopathy progression. 5 Advanced glycation end products (AGEs), kinds of oxidative derivatives resulting from diabetic hyperglycaemia, are known to contribute to the complications of DM by raising intracellular oxidative stress. 6 Extracellular AGEs induce cellular oxidative stress, inflammation and apoptosis in DM complications such as cardiovascular disease and chronic kidney disease.…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone attenuates advanced glycation end products‐induced apoptosis and calcification by modulating autophagy in tendon‐derived stem cells

et al. 2020

J Cellular Molecular Medi

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Diabetes mellitus (DM) is one of the prominent risk factors for pathological development and progression of tendinopathy. One feature of DM-related changes in tendinopathy is accumulation of advanced glycation end products (AGEs) in affected tendons.Pioglitazone (Pio), a peroxisome proliferator-activated receptor γ agonist, performs a protective effect against AGEs. The present study aimed to investigate the pathogenetic role of AGEs on tendon-derived stem cells (TDSCs) and to determine the effect of Pio on AGEs-induced TDSC dysfunctions. Results indicated that AGEs induced TDSC apoptosis as well as compensatory activation of autophagy. Pharmacologic activation/ inhibition of autophagy leaded to alleviate/exacerbate apoptosis induced by AGEs. We further confirmed the effect of Pio on autophagy, which ameliorated apoptosis and abnormal calcification caused by AGEs both in vitro and in vivo. Thus, we suggest that Pio ameliorates the dysfunctions of TDSCs against AGEs by promoting autophagy, and we also reveal that Pio is a potential pharmacological choice for tendinopathy. K E Y W O R D Sadvanced glycation end products, apoptosis, autophagy, pioglitazone, tendon-derived stem cells

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“…Similarly, the in vitro multipotency of TPCs isolated from injured tendon is restricted and shifts towards a chondroosteogenic phenotype [17,19]. A recent study by Shi et al demonstrated that TPCs isolated from DM have a decreased tenogenic phenotype and express higher levels of chondroosteogenic genes [20]. Taken together, aberrant differentiation of TPCs under the influence of pathological stimuli present in DM may be responsible for pathological calcified tissue present in injured/healing tendon.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, systemic hyperinsulinemia secondary to impaired insulin sensitivity can occur during early DM. While the tenogenic phenotype of TPCs in injured DM tendon tissue and during in vitro culture with high-glucose concentration is significantly decreased, the effects of highinsulin concentrations on TPCs have not been investigated [20,21]. Both exogenous insulin and recombinant insulinlike growth factor-I (IGF-I) increase the in vitro osteogenic capacity of osteoblasts and periodontal ligament fibroblasts [22,23].…”

Section: Introductionmentioning

confidence: 99%

Insulin Enhances the In Vitro Osteogenic Capacity of Flexor Tendon-Derived Progenitor Cells

Durgam

Altmann

Coughlin

et al. 2019

Stem Cells International

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There is increased incidence of tendon disorders and decreased tendon healing capacity in people with diabetes mellitus (DM). Recent studies have also suggested pathological ossification in repair tendon of people with DM. Therefore, the objective of this study is to investigate the effects of insulin supplementation, an important pathophysiologic stimulus of DM, on tendon progenitor cell (TPC) proliferation and in vitro osteogenic capacity. Passage 3 TPCs were isolated from collagenase-digested, equine superficial digital flexor tendons. TPC proliferation was measured via MTT assay after 3 days of monolayer culture in medium supplemented with 0, 0.007, 0.07, and 0.7 nM insulin. In vitro osteogenic capacity of TPCs (Alizarin Red staining, osteogenic mRNA expression, and alkaline phosphatase bioactivity) was assessed with 0, 0.07, and 0.7 nM insulin-supplemented osteogenic induction medium. Insulin (0.7 nM) significantly increased TPC proliferation after 3 days of monolayer culture. Alizarin Red staining of insulin-treated TPC osteogenic cultures demonstrated robust cell aggregation and mineralized matrix secretion, in a dose-dependent manner. Runx2, alkaline phosphatase, and Osteonectin mRNA and alkaline phosphatase bioactivity of insulin-treated TPC cultures were significantly higher at day 14 of osteogenesis compared to untreated controls. Addition of picropodophyllin (PPP), a selective IGF-I receptor inhibitor, mitigated the increased osteogenic capacity of TPCs, indicating that IGF-I signaling plays an important role. Our findings indicate that hyperinsulinemia may alter TPC phenotype and subsequently impact the quality of repair tendon tissue.

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Impaired function of tendon-derived stem cells in experimental diabetes mellitus rat tendons: implications for cellular mechanism of diabetic tendon disorder

Cited by 19 publications

References 37 publications

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

Pioglitazone attenuates advanced glycation end products‐induced apoptosis and calcification by modulating autophagy in tendon‐derived stem cells

Insulin Enhances the In Vitro Osteogenic Capacity of Flexor Tendon-Derived Progenitor Cells

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