NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations DOI Creative Commons
Liang Yang,

Zifeng Ruan,

Xiaobing Lin

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 16, 2024

Abstract Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation mitochondrial DNA (mtDNA) mutations. However, little known about how accumulated mtDNA mutations modulate homeostasis. We observe the small intestine aged male mice, suggesting association with physiological aging. Using polymerase gamma (POLG) mutator mice wild-type we generate progressive mutation burdens. Investigation utilizing organoid technology vivo stem cell labeling reveals decreased colony formation efficiency crypts LGR5-expressing cells response to a threshold burden. Mechanistically, increased burden exacerbates aging phenotype through ATF5 dependent unfolded protein (UPR mt ) activation. This reversed supplementation NAD + precursor, NMN. Thus, uncover UPR triggered that regulates

Language: Английский

Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies DOI Creative Commons
Junjun Jing,

Zhuoxuan Wu,

Jiahe Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 18, 2023

Abstract The past decade has seen significant advances in our understanding of Hedgehog (HH) signaling pathway various biological events. HH exerts its effects through a complex cascade involved with primary cilium. important functions embryonic development and tissue homeostasis. It plays central role the regulation proliferation differentiation adult stem cells. Importantly, it become increasingly clear that is associated increased cancer prevalence, malignant progression, poor prognosis even mortality. Understanding integrative nature opened up potential for new therapeutic targets cancer. A variety drugs have been developed, including small molecule inhibitors, natural compounds, long non-coding RNA (LncRNA), some which are approved clinical use. This review outlines recent discoveries homeostasis discusses how these paving way biologically based therapies Furthermore, we address status quo limitations targeted pathway. Insights from this will help readers understand function cancer, as well opportunities challenges

Language: Английский

Citations

82
An oncogenic phenoscape of colonic stem cell polarization DOI Creative Commons
Xiao Qin, Ferran Cardoso Rodriguez, Jahangir Sufi

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(25), P. 5554 - 5568.e18

Published: Dec. 1, 2023

Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes often studied separately. To functionally map how cell-intrinsic cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures (1) colorectal cancer (CRC) mutations, (2) fibroblasts macrophages, (3) stromal ligands, (4) signaling inhibitors. Multiplexed revealed stepwise epithelial differentiation phenoscape dictated combinations oncogenes spanning from fibroblast-induced Clusterin (CLU)+ revival stem (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition revCSCs proCSCs is decreasing WNT3A TGF-β-driven YAP increasing KRASG12D or EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss collaboratively limit access disrupt stromal-epithelial communication—trapping epithelia in the proCSC fate. These results reveal dominate homeostatic obstructing regulation cell-fate plasticity.

Language: Английский

Citations

45
SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys DOI
Shikhar Aggarwal, Zhanxiang Wang, David Rincon Fernandez Pacheco

et al.

Science, Journal Year: 2024, Volume and Issue: 383(6685)

Published: Feb. 22, 2024

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach head-to-head comparison of injury-induced lineages, we identified dynamic switch in repairing epithelia. Lineages that regenerated epithelia silenced and healed (SOX9

Language: Английский

Citations

34
Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling DOI
Paolo Cadinu, Kisha N. Sivanathan, A. Misra

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(8), P. 2010 - 2028.e30

Published: April 1, 2024

Language: Английский

Citations

29
NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations DOI Creative Commons
Liang Yang,

Zifeng Ruan,

Xiaobing Lin

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 16, 2024

Abstract Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation mitochondrial DNA (mtDNA) mutations. However, little known about how accumulated mtDNA mutations modulate homeostasis. We observe the small intestine aged male mice, suggesting association with physiological aging. Using polymerase gamma (POLG) mutator mice wild-type we generate progressive mutation burdens. Investigation utilizing organoid technology vivo stem cell labeling reveals decreased colony formation efficiency crypts LGR5-expressing cells response to a threshold burden. Mechanistically, increased burden exacerbates aging phenotype through ATF5 dependent unfolded protein (UPR mt ) activation. This reversed supplementation NAD + precursor, NMN. Thus, uncover UPR triggered that regulates

Language: Английский

Citations

21