Microenvironmental control of hematopoietic stem cell fate via CXCL8 and protein kinase C

被引：7

作者：

Binder, Vera ^{[1
]}

Li, Wantong ^{[2
,3
]}

Faisal, Muhammad ^{[2
,3
]}

Oyman, Konur ^{[2
,3
]}

Calkins, Donn L. ^{[2
,3
]}

Shaffer, Jami ^{[2
,3
]}

Teets, Emily M. ^{[2
,3
]}

Sher, Steven ^{[2
,3
]}

Magnotte, Andrew ^{[2
,3
]}

Belardo, Alex ^{[2
,3
]}

Deruelle, William ^{[2
,3
]}

Gregory, T. Charles ^{[2
,3
,4
]}

Orwick, Shelley ^{[2
,3
]}

Hagedorn, Elliott J. ^{[5
]}

Perlin, Julie R. ^{[6
,7
]}

Avagyan, Serine ^{[8
]}

Lichtig, Asher ^{[6
,7
]}

Barrett, Francesca ^{[6
,7
]}

Ammerman, Michelle ^{[6
,7
]}

Yang, Song ^{[6
,7
]}

Zhou, Yi ^{[6
,7
]}

Carson, William E. ^{[3
]}

Shive, Heather R. ^{[9
]}

Blachly, James S. ^{[2
,3
,4
]}

Lapalombella, Rosa ^{[2
,3
]}

Zon, Leonard I. ^{[6
,7
,8
,10
,11
]}

Blaser, Bradley W. ^{[2
,3
]}

机构：

[1] Ludwig Maximillians Univ, Dr von Hauner Childrens Hosp, Dept Pediat Hematol Oncol, Univ Hosp, D-80337 Munich, Germany

[2] Ohio State Univ, Dept Internal Med, Div Hematol, Coll Med, Columbus, OH 43210 USA

[3] Ohio State Univ, James Canc Hosp & Solove Res Inst, Comprehens Canc Ctr, Columbus, OH 43210 USA

[4] Ohio State Univ, Dept Biomed Informat, Coll Med, Columbus, OH 43210 USA

[5] Boston Univ, Dept Med, Sch Med, Boston, MA 02118 USA

[6] Boston Childrens Hosp, Stem Cell Program, Div Hematol Oncol, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Boston, MA 02115 USA

[8] Dana Farber Boston Childrens Hosp Canc & Blood Dis, Boston, MA 02115 USA

[9] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA

[10] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[11] Harvard Univ, Stem Cell & Regenerat Biol Dept, Cambridge, MA 02138 USA

来源：

CELL REPORTS | 2023年 / 42卷 / 05期

关键词：

BRUTONS TYROSINE KINASE; TUMOR SUPPRESSOR WT1; CLONAL HEMATOPOIESIS; ENDOTHELIAL-CELLS; VASCULAR NICHE; SELF-RENEWAL; ADULT ZEBRAFISH; KAPPA-B; EXPRESSION; ENGRAFTMENT;

D O I：

10.1016/j.celrep.2023.112528

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Altered hematopoietic stem cell (HSC) fate underlies primary blood disorders but microenvironmental factors controlling this are poorly understood. Genetically barcoded genome editing of synthetic target arrays for lineage tracing (GESTALT) zebrafish were used to screen for factors expressed by the sinusoidal vascular niche that alter the phylogenetic distribution of the HSC pool under native conditions. Dysregulated expres-sion of protein kinase C delta (PKC-8, encoded by prkcda) increases the number of HSC clones by up to 80% and expands polyclonal populations of immature neutrophil and erythroid precursors. PKC agonists such as cxcl8 augment HSC competition for residency within the niche and expand defined niche populations. CXCL8 induces association of PKC-8 with the focal adhesion complex, activating extracellular signal-regulated ki-nase (ERK) signaling and expression of niche factors in human endothelial cells. Our findings demonstrate the existence of reserve capacity within the niche that is controlled by CXCL8 and PKC and has significant impact on HSC phylogenetic and phenotypic fate.

引用

页数：27

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