Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP)...Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP).These pathways act as a Yin-Yang system,balancing beneficial and detrimental outcomes across development,tissue homeostasis,and disease.On the yin(protective)side,transient ISR activation and acute SASP signaling foster adaptation,embryonic patterning,wound healing,and regeneration.On the yang(maladaptive)side,chronic ISR signaling and unresolved SASP output drive stem cell exhaustion,fibrosis,inflammation,and tumorigenesis.This duality highlights their roles as both guardians and disruptors of stem cell integrity.Mechanistically,ISR regulates translational control via eukaryotic initiation factor 2 alpha(eIF2α)phosphorylation and activating transcription factor 4(ATF4)-dependent transcription,while SASP reprograms the extracellular milieu through cytokines,growth factors,and proteases.Their crosstalk creates feedback loops that shape tissue niches and long-termstemcell potential.Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline,to offer new insights into regenerative medicine,anti-aging interventions,and cancer therapeutics.展开更多
Senescence is a cell fate that can be induced by intra/extracellular stresses such as DNA damage,oncogenic mutations,telomere shorting,and inflammation[1].Senescent cells develop a characteristic secretion profile inc...Senescence is a cell fate that can be induced by intra/extracellular stresses such as DNA damage,oncogenic mutations,telomere shorting,and inflammation[1].Senescent cells develop a characteristic secretion profile including a range of cytokines,chemokines,proteases,and other factors,which is termed the senescence-associated secretory phenotype(SASP)[2].Accumulating evidence indicates that SASP factors provoke multiple chronic diseases,even tumorigenesis and aggressiveness[3].Our recent studies reveal that heavy ion could induce senescence with lower dose than X-ray in various tumor cells[4;5].However,very little is known about the SASP of senescent tumor cells induced by heavy ions.In the present study,human melanoma cell line 92-1 cells were exposed to 10 Gy of carbon ion beams or X-rays,respectively.The cell culture supernatants were harvested 3 days post-irradiation,and the SASP were measured using human antibody arrays including 507 factors.展开更多
基金funded by the National Institutes of Health,grant numbers UG3OD023285,P42ES030991,and P30ES036084.
文摘Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP).These pathways act as a Yin-Yang system,balancing beneficial and detrimental outcomes across development,tissue homeostasis,and disease.On the yin(protective)side,transient ISR activation and acute SASP signaling foster adaptation,embryonic patterning,wound healing,and regeneration.On the yang(maladaptive)side,chronic ISR signaling and unresolved SASP output drive stem cell exhaustion,fibrosis,inflammation,and tumorigenesis.This duality highlights their roles as both guardians and disruptors of stem cell integrity.Mechanistically,ISR regulates translational control via eukaryotic initiation factor 2 alpha(eIF2α)phosphorylation and activating transcription factor 4(ATF4)-dependent transcription,while SASP reprograms the extracellular milieu through cytokines,growth factors,and proteases.Their crosstalk creates feedback loops that shape tissue niches and long-termstemcell potential.Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline,to offer new insights into regenerative medicine,anti-aging interventions,and cancer therapeutics.
文摘Senescence is a cell fate that can be induced by intra/extracellular stresses such as DNA damage,oncogenic mutations,telomere shorting,and inflammation[1].Senescent cells develop a characteristic secretion profile including a range of cytokines,chemokines,proteases,and other factors,which is termed the senescence-associated secretory phenotype(SASP)[2].Accumulating evidence indicates that SASP factors provoke multiple chronic diseases,even tumorigenesis and aggressiveness[3].Our recent studies reveal that heavy ion could induce senescence with lower dose than X-ray in various tumor cells[4;5].However,very little is known about the SASP of senescent tumor cells induced by heavy ions.In the present study,human melanoma cell line 92-1 cells were exposed to 10 Gy of carbon ion beams or X-rays,respectively.The cell culture supernatants were harvested 3 days post-irradiation,and the SASP were measured using human antibody arrays including 507 factors.
