Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to ...Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.展开更多
基金supported by the National Natural Science Foundation of China(32372247)the National Key Research and Development Program of China(2023YFF1104501)to Huiyuan Guo.
文摘Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.
