Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells

Abstract

Aims: Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs). Results: We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCBMSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP-1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB-MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1. Innovation: Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype. Conclusion: Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1. Antioxid. Redox Signal. 24, 471-485.

An early‐senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro‐inflammatory program

“…In particular, MCP1 was among the most highly expressed SASP factors in aged MSC both at the transcript and protein levels. Consistent with these findings, MCP1 was reported to be epigenetically repressed in umbilical cord blood‐derived MSC and activated only when cells reach premature senescence due to prolonged culture conditions (Jin et al, ).…”

MiR-495 Promotes Senescence of Mesenchymal Stem Cells by Targeting Bmi-1

“…Bmi-1 could also promote glioma angiogenesis by activating NF-κB signaling [58]. What’s more, UCB-MSCs (umbilical cord blood derived MSCs) exhibited the typical senescent phenotype when knocked down Bmi-1 [59]. In our current study, we found that Bmi-1 was lowly expressed in the umbilical cord tissues and MSCs derived from PE compared with healthy pregnancies while miR-495 was highly expressed.…”

Circulating levels of monocyte chemoattractant protein‐1 as a potential measure of biological age in mice and frailty in humans

“…Numerous studies previously demonstrated that plasma levels of MCP‐1 correlate with chronologic age in humans (Brouwers et al., ; Deo et al., ; Inadera, Egashira, Takemoto, Ouchi & Matsushima, ; Mansfield et al., ; Pinke et al., ; Scully et al., ) and mice (Chiao et al., ). Monocyte chemoattractant protein‐1 is a senescence‐associated secretory phenotype (SASP) factor secreted by senescent cells (Jin et al., ). Senescence‐associated secretory phenotype can promote secondary senescence in healthy cells (Coppe, Desprez, Krtolica & Campisi, ), and senescent cells have been demonstrated to promote aging and age‐related disease (Baker et al., , ; Zhu et al., ).…”

“…This is supported by data in both mice and humans. MCP‐1 is a SASP factor secreted by senescent cells (Jin et al., ). Senescent cells and the pro‐inflammatory cytokines that they secrete negatively affect tissue homeostasis and repair, leading to organ dysfunction and aging (van Deursen, ).…”