Three-dimensional self-assembling nanofiber matrix rejuvenates aged/degenerative human tendon stem/progenitor cells

Yin, Heyong; Strunz, Franziska; Zhi-yong, Yan; Lü, Jiaju; Brochhausen, Christoph; Kiderlen, Stefanie; Clausen‐Schaumann, Hauke; Wang, Xiumei; Gomes, Manuela E.; Alt, Volker; Docheva, Denitsa

doi:10.1016/j.biomaterials.2020.119802

Cited by 46 publications

(34 citation statements)

References 40 publications

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“…The structural and biomechanical properties of the ECM can profoundly affect cell behavior. Interestingly, providing A-TSPCs with hydrogel environment consisting of aligned nanonfibers alleviated their aged phenotype (Yin et al, 2020). Hence, "engineering a healthy" ECM niche might be an attractive way to rejuvenate aged cells, support their growth and direct their fate decision and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Zhi-yong

Yin

Brochhausen

et al. 2020

Front. Bioeng. Biotechnol.

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Tendons are dense connective tissues, which are critical for the integrity and function of our musculoskeletal system. During tendon aging and degeneration, tendon stem/progenitor cells (TSPCs) experience profound phenotypic changes with declined cellular functions that can be linked to the known increase in complications during tendon healing process in elderly patients. Tissue engineering is a promising approach for achieving a complete recovery of injured tendons. However, use of autologous cells from aged individuals would require restoring the cellular fitness prior to implantation. In this study, we applied an established cell sheet model for in vitro tenogenesis and compared the sheet formation of TSPC derived from young/healthy (Y-TSPCs) versus aged/degenerative (A-TSPCs) human Achilles tendon biopsies with the purpose to unravel differences in their potential to form self-assembled three-dimensional (3D) tendon organoids. Using our three-step protocol, 4 donors of Y-TSPCs and 9 donors of A-TSPCs were subjected to cell sheet formation and maturation in a period of 5 weeks. The sheets were then cross evaluated by weight and diameter measurements; quantification of cell density, proliferation, senescence and apoptosis; histomorphometry; gene expression of 48 target genes; and collagen type I protein production. The results revealed very obvious and significant phenotype in A-TSPC sheets characterized by being fragile and thin with poor tissue morphology, and significantly lower cell density and proliferation, but significantly higher levels of the senescence-related gene markers and apoptotic cells. Quantitative gene expression analyses at the mRNA and protein levels, also demonstrated abnormal molecular circuits in the A-TSPC sheets. Taken together, we report for the first time that A-TSPCs exhibit profound deficits in forming 3D tendon tissue organoids, thus making the cell sheet model suitable to investigate the molecular mechanisms involved in tendon aging and degeneration, as well as examining novel pharmacologic strategies for rejuvenation of aged cells.

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Section: Discussionmentioning

confidence: 99%

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Zhi-yong

Yin

Brochhausen

et al. 2020

Front. Bioeng. Biotechnol.

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“…FBS is known to contain different growth factors; however, a previous study 29 with bone marrowderived mesenchymal stem cells cultivated in medium supplemented with FBS versus such medium enriched with The heatmaps for hTSPCs from standard cell culture (prior 3D cultivation) and hTSPCs cultivated for 3 days in COL I hydrogels (without IOPs) are based on data derived from previous publications by our team. 27,28 Communication Biomaterials Science additional growth factors did not reveal that FBS itself can induce tenogenic differentiation. In addition, all study groups were treated equally with FBS, and based on the gene expression profiling in Tables 1 and 2, the effects were related to days of cultivation and to the alignment of the IOPs.…”

Section: Communicationmentioning

confidence: 95%

“…Furthermore, as compared to hTSPCs from standard cell culture ( prior 3D cultivation) and hTSPCs cultivated for 3 days in COL I hydrogels (without IOPs), we have included the corresponding heatmaps in Tables 1 and 2 based on data derived from our previous publications. 27,28 Next, differences in genes showing a significant change in expression at day 7 were expressed as fold change to the COL I-hTSPC group and plotted in Fig. 5C and D. First, our gene expression results indicated that the tenogenic phenotype of hTSPC was stable during culture in all groups since the majority of genes related to other lineages (chondrogenic, adipogenic, osteogenic, myogenic and embryogenic) were neither expressed nor upregulated over time ( Table 2).…”

Section: Communicationmentioning

confidence: 97%

“…The heatmaps for hTSPCs from standard cell culture (prior 3D cultivation) and hTSPCs cultivated for 3 days in COL I hydrogels (without IOPs) are based on data derived from previous publications by our team. 27,28 Fig . 5 (A) Up-regulated genes in the COL I-A/IOPs-hTSPCs group at day 7, and immunofluorescence staining of COL1A1, COL6A1 and SCX is presented in the ESI Fig.…”

Section: Communicationmentioning

confidence: 99%

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An anisotropic nanocomposite hydrogel guides aligned orientation and enhances tenogenesis of human tendon stem/progenitor cells

Yin

Chu

et al. 2021

Biomater. Sci.

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“…TSPCs are essential for effective repair, regeneration, and maintenance of tendon. Previous studies have demonstrated that TSPCs features alter during tendon aging; aged TSPCs premature entry into senescence and exhibit profound self-renewal, migration, and tenogenic differentiation deficits (Kohler et al, 2013;Yin et al, 2020). These age-related changes of TSPCs led to impaired tendon healing and regeneration capacity (Dai et al, 2019;Li et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Xiao

Dai

et al. 2021

Front. Cell Dev. Biol.

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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.

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Three-dimensional self-assembling nanofiber matrix rejuvenates aged/degenerative human tendon stem/progenitor cells

Cited by 46 publications

References 40 publications

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

Aged Tendon Stem/Progenitor Cells Are Less Competent to Form 3D Tendon Organoids Due to Cell Autonomous and Matrix Production Deficits

An anisotropic nanocomposite hydrogel guides aligned orientation and enhances tenogenesis of human tendon stem/progenitor cells

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

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