Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program

Khacho, Mireille; Clark, Alysen; Svoboda, Devon S.; Azzi, Joëlle; MacLaurin, Jason G.; Meghaizel, Cynthia; Sesaki, Hiromi; Lagace, Diane C.; Germain, Marc; Harper, Mary‐Ellen; Park, David; Slack, Ruth S.

doi:10.1016/j.stem.2016.04.015

Cited by 490 publications

(499 citation statements)

References 46 publications

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“…These observations support the speculation that LTB 4 inhibits HLEC VEGFR3 expression through down-regulation of Notch signaling. Notch signaling also plays a fundamental role in cell fate determination (54,55). However, in the current study, we were unable to determine whether high concentrations of LTB 4 alter the maintenance of lymphatic identity.…”

Section: −/−mentioning

confidence: 63%

Leukotriene B ₄ antagonism ameliorates experimental lymphedema

et al. 2017

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Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B 4 (LTB 4 ). LTB 4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB 4 was functionally bimodal: Lower LTB 4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB 4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB 4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB 4 stimulated, whereas high concentrations of LTB 4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1 −/− mice were refractory to the beneficial effects of LTB 4 antagonism, suggesting that LTB 4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB 4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB 4 is a promising drug target for the treatment of acquired lymphedema.

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Section: −/−mentioning

confidence: 63%

Leukotriene B ₄ antagonism ameliorates experimental lymphedema

et al. 2017

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“…Clearance of aged mitochondria promotes self-renewal of hematopoietic, muscle, breast and natural killer cells (Garcia-Prat et al, 2016; Ito et al, 2016; Katajisto et al, 2015; O’Sullivan et al, 2015). Mitochondrial biogenesis (Bengsch et al, 2016; Scharping et al, 2016) and fusion (Buck et al, 2016; Khacho et al, 2016; Luchsinger et al, 2016) also supports self-renewal of hematopoietic, neural, and memory T cells. Mitochondrial clearance, biogenesis, and fusion seemingly facilitate cellular self-renewal by eliminating dysfunctional organelles, making new organelles, and fusing nascent mitochondria to optimize efficiency of oxidative metabolism.…”

Section: Discussionmentioning

confidence: 99%

Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal

et al. 2016

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SUMMARY Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa.

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“…Namely, excessive ROS accumulation induces NRF2 activation through KEAP1 inactivation, which leads to the activation and differentiation of HSCs and eventually causes their exhaustion. Indeed, ROS elevation is considered to activate NRF2 for the proliferation of airway basal stem cells (20), and mitochondrial dynamics modify ROS signaling and activate NRF2, which suppresses the self-renewal of neural stem cells (39). Thus, NRF2 might contribute to HSC dysfunction when high levels of ROS accumulate in HSCs, as in deficiencies of Foxo3a, Atm, and Tsc (35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

Murakami

Suzuki

Harigae

et al. 2017

Molecular and Cellular Biology

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Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used Keap1-deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to Keap1 deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response.

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Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program

Cited by 490 publications

References 46 publications

Leukotriene B ₄ antagonism ameliorates experimental lymphedema

Leukotriene B ₄ antagonism ameliorates experimental lymphedema

Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

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Mitochondrial Dynamics Impacts Stem Cell Identity and Fate Decisions by Regulating a Nuclear Transcriptional Program

Cited by 490 publications

References 46 publications

Leukotriene B 4 antagonism ameliorates experimental lymphedema

Leukotriene B 4 antagonism ameliorates experimental lymphedema

Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells

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Product

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Leukotriene B ₄ antagonism ameliorates experimental lymphedema

Leukotriene B ₄ antagonism ameliorates experimental lymphedema