title: Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration.
abstract: Although the link between altered stem cell properties and tissue aging has been recognized, the molecular and cellular processes of tendon aging have not been elucidated. As tendons contain stem/progenitor cells (TSPC), we investigated whether the molecular and cellular attributes of TSPC alter during tendon aging and degeneration. Comparing TSPC derived from young/healthy (Y-TSPC) and aged/degenerated human Achilles tendon biopsies (A-TSPC), we observed that A-TSPC exhibit a profound self-renewal and clonogenic deficits, while their multipotency was still retained. Senescence analysis showed a premature entry into senescence of the A-TSPC, a finding accompanied by an upregulation of p16(INK4A). To identify age-related molecular factors, we performed microarray and gene ontology analyses. These analyses revealed an intriguing transcriptomal shift in A-TSPC, where the most differentially expressed probesets encode for genes regulating cell adhesion, migration, and actin cytoskeleton. Time-lapse analysis showed that A-TSPC exhibit decelerated motion and delayed wound closure concomitant to a higher actin stress fiber content and a slower turnover of actin filaments. Lastly, based on the expression analyses of microarray candidates, we suggest that dysregulated cell-matrix interactions and the ROCK kinase pathway might be key players in TSPC aging. Taken together, we propose that during tendon aging and degeneration, the TSPC pool is becoming exhausted in terms of size and functional fitness. Thus, our study provides the first fundamental basis for further exploration into the molecular mechanisms behind tendon aging and degeneration as well as for the selection of novel tendon-specific therapeutical targets.
authors.affiliation: Department of Surgery, Experimental Surgery and Regenerative Medicine, Ludwig Maximilians University Munich, Nussbaumstr. 20, 80336, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kohler
authors.forename: Cvetan
authors.initials: C
authors.lastname: Popov
authors.forename: Barbara
authors.initials: B
authors.lastname: Klotz
authors.forename: Paolo
authors.initials: P
authors.lastname: Alberton
authors.forename: Wolf Christian
authors.initials: WC
authors.lastname: Prall
authors.forename: Florian
authors.initials: F
authors.lastname: Haasters
authors.forename: Sigrid
authors.initials: S
authors.lastname: Müller-Deubert
authors.forename: Regina
authors.initials: R
authors.lastname: Ebert
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
authors.forename: Matthias
authors.initials: M
authors.lastname: Schieker
authors.forename: Denitsa
authors.initials: D
authors.lastname: Docheva
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000328:Adult; D000375:Aging / Q000473:pathology*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D048429:Cell Size; D016922:Cellular Senescence; D005109:Extracellular Matrix / Q000378:metabolism; D063990:Gene Ontology; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology*; D013710:Tendons / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D016023:Integrins; D054460:rho-Associated Kinases
keywords: ROCK kinase; actin dynamics; cell-matrix interactions; microarray; senescence; tendon stem/progenitor cells