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

Minhao Chen; Longfei Xiao; Guangchun Dai; Panpan Lu; Yuanwei Zhang; Yingjuan Li; Ming Ni; Yunfeng Rui

doi:10.3389/fcell.2021.650250

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

Front Cell Dev Biol. 2021 Mar 29:9:650250. doi: 10.3389/fcell.2021.650250. eCollection 2021.

Authors

Minhao Chen^{1

2

3}, Longfei Xiao^{1

2

3}, Guangchun Dai^{1

2

3}, Panpan Lu^{1

2

3}, Yuanwei Zhang^{1

2

3}, Yingjuan Li⁴, Ming Ni⁵, Yunfeng Rui^{1

2

3

6}

Affiliations

¹ Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
² Orthopaedic Trauma Institute (OTI), Southeast University, Nanjing, China.
³ Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
⁴ Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
⁵ Department of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing, China.
⁶ China Orthopedic Regenerative Medicine Group, Hangzhou, China.

Abstract

Diminished regeneration or healing capacity of tendon occurs during aging. It has been well demonstrated that tendon stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and repair. Here, we identified an accumulation of senescent TSPCs in tendon tissue with aging. In aged TSPCs, the activity of JAK-STAT signaling pathway was increased. Besides, genetic knockdown of JAK2 or STAT3 significantly attenuated TSPC senescence in aged TSPCs. Pharmacological inhibition of JAK-STAT signaling pathway with AG490 similarly attenuated cellular senescence and senescence-associated secretory phenotype (SASP) of aged TSPCs. In addition, inhibition of JAK-STAT signaling pathway also restored the age-related dysfunctions of TSPCs, including self-renewal, migration, actin dynamics, and stemness. Together, our findings reveal the critical role of JAK-STAT signaling pathway in the regulation of TSPC aging and suggest an ideal therapeutic target for the age-related tendon disorders.

Keywords: AG490; JAK-STAT signaling pathway; senescence; tendon aging; tendon-derived stem/progenitor cells.