A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate

被引：19

作者：

Bonora, Massimo ^{[1
,2
,3
,4
]}

Morganti, Claudia ^{[1
,2
,3
,4
]}

van Gastel, Nick ^{[5
,6
,7
]}

Ito, Kyoko ^{[1
,2
,3
,4
]}

Calura, Enrica ^{[8
]}

Zanolla, Ilaria ^{[9
]}

Ferroni, Letizia ^{[10
]}

Zhang, Yang ^{[11
]}

Jung, Yookyung ^{[11
,12
,13
]}

Sales, Gabriele ^{[8
]}

Martini, Paolo ^{[14
]}

Nakamura, Takahisa ^{[15
,16
,17
,18
]}

Lasorsa, Francesco Massimo ^{[19
,20
]}

Finkel, Toren ^{[21
,22
]}

Lin, Charles P. ^{[23
,24
]}

Zavan, Barbara ^{[10
,25
,26
]}

Pinton, Paolo ^{[9
,10
]}

Georgakoudi, Irene ^{[11
]}

Romualdi, Chiara ^{[8
]}

Scadden, David T. ^{[5
,6
]}

Ito, Keisuke ^{[1
,2
,3
,4
,27
,28
]}

机构：

[1] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regene, 1300 Morris Pk Ave, Bronx, NY 10461 USA

[2] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA

[3] Montefiore Hlth Syst, Albert Einstein Coll Med, Dept Oncol, Bronx, NY 10461 USA

[4] Montefiore Hlth Syst, Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA

[5] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA USA

[6] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA USA

[7] UCLouvain, Duve Inst, B-1200 Brussels, Belgium

[8] Univ Padua, Dept Biol, I-35121 Padua, Italy

[9] Univ Ferrara, Dept Med Sci, I-44121 Ferrara, Italy

[10] Maria Cecilia Hosp, GVM Care & Res, I-48033 Cotignola, Ravenna, Italy

[11] Tufts Univ, Dept Biomed Engn, 4 Colby St, Medford, MA 02155 USA

[12] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA

[13] Albert Einstein Coll Med, Gruss Lipper Biophoton Ctr, Bronx, NY 10461 USA

[14] Univ Brescia, Dept Mol & Translat Med, I-25121 Brescia, Italy

[15] Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati, OH 45229 USA

[16] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA

[17] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA

[18] Tohoku Univ, Inst Dev Aging & Canc, Dept Metab Bioregulat, Sendai 9808575, Japan

[19] Univ Bari, Dept Biosci Biotechnol & Environm, I-70125 Bari, Italy

[20] CNR, Inst Biomembranes Bioenerget & Mol Biotechnol, I-70125 Bari, Italy

[21] Univ Pittsburgh, Aging Inst, Med Ctr, Pittsburgh, PA 15261 USA

[22] Univ Pittsburgh, Med Ctr, Dept Med, Sch Med, Pittsburgh, PA 15261 USA

[23] Harvard Med Sch, Ctr Syst Biol, Boston, MA 02114 USA

[24] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA

[25] Univ Ferrara, Lab Technol Adv Therapies LTTA, I-44121 Ferrara, Italy

[26] Univ Ferrara, Translat Med Dept, I-44121 Ferrara, Italy

[27] Albert Einstein Coll Med, Montefiore Einstein Comprehens Canc Ctr, Bronx, NY 10461 USA

[28] Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10461 USA

来源：

CELL STEM CELL | 2024年 / 31卷 / 03期

关键词：

ACID OXIDATION; PATHWAY; METABOLISM; MAINTAINS; MEMBRANES; TOOL; MICROVESICLES; CARBOXYLATION; PROGENITORS; ASSOCIATION;

D O I：

10.1016/j.stem.2024.02.004

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self -renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO -generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC selfrenewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non -stochastic nature of HSC fate determination.

引用

页码：359 / 377.e10

页数：30

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