Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells
Vivian Y. Chang,
Yuwei He,
Samantha Grohe,
Morgan R. Brady,
Aldi Chan,
Rucha S. Kadam,
Tiancheng Fang,
Amara Pang,
Katherine Pohl,
Evelyn Tran,
Michelle Li,
Jenny Kan,
Yurun Zhang,
Josie J. Lu,
Joshua P. Sasine,
Heather A. Himburg,
Peibin Yue,
John P. Chute
Affiliations
Vivian Y. Chang
Division of Hematology-Oncology, Department of Pediatrics, UCLA, Los Angeles, CA, USA; Children’s Discovery and Innovation Institute, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
Yuwei He
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
Samantha Grohe
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
Morgan R. Brady
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
Aldi Chan
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
Rucha S. Kadam
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
Tiancheng Fang
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
Amara Pang
Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Katherine Pohl
Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Evelyn Tran
Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Michelle Li
Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Jenny Kan
Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Yurun Zhang
Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA
Josie J. Lu
Applied Genomics, Computation and Translational Core, Cedars Sinai Medical Center, Los Angeles, CA, USA
Joshua P. Sasine
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
Heather A. Himburg
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
Peibin Yue
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
John P. Chute
Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, Los Angeles, CA 90095, USA; Samuel Oschin Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA 90095, USA; Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 91361, USA; Corresponding author
Summary: Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.
