Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling

Cells. 2021 Jan 3;10(1):63. doi: 10.3390/cells10010063.


In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.

Keywords: C-X-C motif chemokine receptor 2; cell-based therapy; growth-regulated oncogene-alpha; interukin-8; mesenchymal stem cell senescence; senescence-associated secretory phenotype; small cell; toll-like receptor 2; toll-like receptor 5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autocrine Communication
  • Cell Size*
  • Cellular Senescence*
  • Chemokine CXCL1 / metabolism
  • Fetal Blood / cytology
  • Humans
  • Infant, Newborn
  • Inflammation Mediators / metabolism
  • Interleukin-8 / metabolism
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism*
  • Phenotype
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction*
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 5 / metabolism*


  • Chemokine CXCL1
  • Inflammation Mediators
  • Interleukin-8
  • Receptors, Interleukin-8B
  • Toll-Like Receptor 2
  • Toll-Like Receptor 5