BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage.However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells(BMSCs),is...BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage.However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells(BMSCs),is less reported.BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis;however,the impairment caused by sepsis remains unknown.AIM To investigate the effects of sepsis on BMSCs and the underlying mechanisms.METHODS BMSCs were obtained from healthy donors and patients with sepsis.We compared the self-renewal capacity,differentiation potential,and hematopoietic supportive ability in vitro.Senescence of septic BMSCs was assessed usingβ-galactosidase staining,senescence-associated secretory phenotype,intracellular reactive oxygen species levels,and the expression of P16 and P21.Finally,the changes in septic BMSCs after nicotinamide adenine dinucleotide(NAD)treatment were evaluated.RESULTS Septic BMSCs showed decreased proliferation and self-renewal,bias towards adipogenic differentiation,and weakened osteogenic differentiation.Additionally,hematopoietic supportive capacity declines in sepsis.The levels of aging markers were significantly higher in the septic BMSCs.After NAD treatment,the proliferation capacity of septic BMSCs showed a recovery trend,with increased osteogenic and hematopoietic supportive capacities.Sepsis resulted in decreased expression of sirtuin 3(SIRT3)in BMSCs,whereas NAD treatment restored SIRT3 expression,enhanced superoxide dismutase enzyme activity,reduced intracellular reactive oxygen species levels,maintained mitochondrial stability and function,and ultimately rejuvenated septic BMSCs.CONCLUSION Sepsis accelerates the aging of BMSCs,as evidenced by a decline in self-renewal and osteogenic capabilities,as well as weakened hematopoietic support functions.These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway.展开更多
基金Shanghai Natural Science Foundation,No.21ZR1452300the Clinical Research Innovation Plan of Shanghai General Hospital,No.CCTR-2022B04.
文摘BACKGROUND Sepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage.However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells(BMSCs),is less reported.BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis;however,the impairment caused by sepsis remains unknown.AIM To investigate the effects of sepsis on BMSCs and the underlying mechanisms.METHODS BMSCs were obtained from healthy donors and patients with sepsis.We compared the self-renewal capacity,differentiation potential,and hematopoietic supportive ability in vitro.Senescence of septic BMSCs was assessed usingβ-galactosidase staining,senescence-associated secretory phenotype,intracellular reactive oxygen species levels,and the expression of P16 and P21.Finally,the changes in septic BMSCs after nicotinamide adenine dinucleotide(NAD)treatment were evaluated.RESULTS Septic BMSCs showed decreased proliferation and self-renewal,bias towards adipogenic differentiation,and weakened osteogenic differentiation.Additionally,hematopoietic supportive capacity declines in sepsis.The levels of aging markers were significantly higher in the septic BMSCs.After NAD treatment,the proliferation capacity of septic BMSCs showed a recovery trend,with increased osteogenic and hematopoietic supportive capacities.Sepsis resulted in decreased expression of sirtuin 3(SIRT3)in BMSCs,whereas NAD treatment restored SIRT3 expression,enhanced superoxide dismutase enzyme activity,reduced intracellular reactive oxygen species levels,maintained mitochondrial stability and function,and ultimately rejuvenated septic BMSCs.CONCLUSION Sepsis accelerates the aging of BMSCs,as evidenced by a decline in self-renewal and osteogenic capabilities,as well as weakened hematopoietic support functions.These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway.
