Cell Reports (May 2023)
Microenvironmental control of hematopoietic stem cell fate via CXCL8 and protein kinase C
- Vera Binder,
- Wantong Li,
- Muhammad Faisal,
- Konur Oyman,
- Donn L. Calkins,
- Jami Shaffer,
- Emily M. Teets,
- Steven Sher,
- Andrew Magnotte,
- Alex Belardo,
- William Deruelle,
- T. Charles Gregory,
- Shelley Orwick,
- Elliott J. Hagedorn,
- Julie R. Perlin,
- Serine Avagyan,
- Asher Lichtig,
- Francesca Barrett,
- Michelle Ammerman,
- Song Yang,
- Yi Zhou,
- William E. Carson,
- Heather R. Shive,
- James S. Blachly,
- Rosa Lapalombella,
- Leonard I. Zon,
- Bradley W. Blaser
Affiliations
- Vera Binder
- Dr. von Hauner Childrens’ Hospital, University Hospital Ludwig Maximillian’s University, Department of Pediatric Hematology/Oncology, 80337 Munich, Germany
- Wantong Li
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Muhammad Faisal
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Konur Oyman
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Donn L. Calkins
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Jami Shaffer
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Emily M. Teets
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Steven Sher
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Andrew Magnotte
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Alex Belardo
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- William Deruelle
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- T. Charles Gregory
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA; The Ohio State University College of Medicine, Department of Biomedical Informatics, Columbus, OH 43210, USA
- Shelley Orwick
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Elliott J. Hagedorn
- Boston University School of Medicine, Department of Medicine, Boston, MA 02118, USA
- Julie R. Perlin
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA
- Serine Avagyan
- Dana-Farber/Boston Children’s Hospital Cancer and Blood Disorders Center, Boston, MA 02115, USA
- Asher Lichtig
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA
- Francesca Barrett
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA
- Michelle Ammerman
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA
- Song Yang
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA
- Yi Zhou
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA
- William E. Carson
- The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Heather R. Shive
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
- James S. Blachly
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA; The Ohio State University College of Medicine, Department of Biomedical Informatics, Columbus, OH 43210, USA
- Rosa Lapalombella
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Leonard I. Zon
- Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Dana-Farber/Boston Children’s Hospital Cancer and Blood Disorders Center, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA
- Bradley W. Blaser
- The Ohio State University College of Medicine, Department of Internal Medicine, Division of Hematology, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 5
p. 112528
Abstract
Summary: 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 expression of protein kinase C delta (PKC-δ, 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-δ with the focal adhesion complex, activating extracellular signal-regulated kinase (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.
