Pappalardo Alberto, Kim Jin Yong, Abaci Hasan Erbil, Christiano Angela M
Department of Dermatology, Columbia University, New York, New York, USA.
Department of Genetics and Development, Columbia University, New York, New York, USA.
Aging Cell. 2025 Jan;24(1):e14353. doi: 10.1111/acel.14353. Epub 2024 Nov 29.
Senescent cells secrete a senescence-associated secretory phenotype (SASP), which can induce senescence in neighboring cells. Human dermal papilla (DP) cells lose their original hair inductive properties when expanded in vitro, and rapidly accumulate senescent cells in culture. Protein and RNA-seq analysis revealed an accumulation of DP-specific SASP factors including IL-6, IL-8, MCP-1, and TIMP-2. We found that combined senolytic treatment of dasatinib and quercetin depleted senescent cells, and reversed SASP accumulation and SASP-mediated repressive interactions in human DP culture, resulting in an increased Wnt-active cell population. In hair reconstitution assays, senolytic-depleted DP cells exhibited restored hair inductive properties by regenerating de novo hair follicles (HFs) compared to untreated DP cells. In 3D skin constructs, senolytic-depleted DP cells enhanced inductive potential and hair lineage specific differentiation of keratinocytes. These data revealed that senolytic treatment of cultured human DP cells markedly increased their inductive potency in HF regeneration, providing a new rationale for clinical applications of senolytic treatment in combination with cell-based therapies.
衰老细胞分泌衰老相关分泌表型（SASP），它可诱导邻近细胞衰老。人真皮乳头（DP）细胞在体外培养扩增时会丧失其原有的毛发生成特性，并在培养过程中迅速积累衰老细胞。蛋白质和RNA测序分析显示，DP特异性SASP因子如白细胞介素-6（IL-6）、白细胞介素-8（IL-8）、单核细胞趋化蛋白-1（MCP-1）和金属蛋白酶组织抑制因子-2（TIMP-2）有所积累。我们发现，达沙替尼和槲皮素联合溶衰老治疗可清除衰老细胞，逆转人DP培养物中SASP的积累以及SASP介导的抑制性相互作用，从而增加Wnt活性细胞群体。在毛发重建试验中，与未处理的DP细胞相比，经溶衰老处理清除衰老细胞的DP细胞通过重新生成新的毛囊（HFs）展现出恢复的毛发生成特性。在3D皮肤构建物中，经溶衰老处理清除衰老细胞的DP细胞增强了角质形成细胞的诱导潜能和毛发谱系特异性分化。这些数据表明，对培养的人DP细胞进行溶衰老治疗可显著提高其在HF再生中的诱导能力，为溶衰老治疗与基于细胞的疗法联合应用于临床提供了新的理论依据。
