Enhanced hematopoietic stem cell function mediates immune regeneration following sex steroid blockade.
Mechanisms underlying age-related defects within lymphoid-lineages remain poorly understood. We previously reported that sex steroid ablation (SSA) induced lymphoid rejuvenation and enhanced recovery from hematopoietic stem cell (HSC) transplantation (HSCT). We herein show that, mechanistically, SSA induces hematopoietic and lymphoid recovery by functionally enhancing both HSC self-renewal and propensity for lymphoid differentiation through intrinsic molecular changes. Our transcriptome analysis revealed further hematopoietic support through rejuvenation of the bone marrow (BM) microenvironment, with upregulation of key hematopoietic factors and master regulatory factors associated with aging such as Foxo1. These studies provide important cellular and molecular insights into understanding how SSA-induced regeneration of the hematopoietic compartment can underpin recovery of the immune system following damaging cytoablative treatments. These findings support a short-term strategy for clinical use of SSA to enhance the production of lymphoid cells and HSC engraftment, leading to improved outcomes in adult patients undergoing HSCT and immune depletion in general.
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Danika M
DM
Khong
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: dudakovj@mskcc.org.
Jarrod A
JA
Dudakov
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Maree V
MV
Hammett
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Marc I
MI
Jurblum
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Sacha M L
SM
Khong
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Gabrielle L
GL
Goldberg
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Tomoo
T
Ueno
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Lisa
L
Spyroglou
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Lauren F
LF
Young
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Marcel R M
MR
van den Brink
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
Richard L
RL
Boyd
Stem Cells and Immune Regeneration Laboratory, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia. Electronic address: ann.chidgey@monash.edu.
Ann P
AP
Chidgey
D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement; D000066673:Cell Self Renewal; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D012739:Gonadal Steroid Hormones / Q000037:antagonists & inhibitors*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D038041:Lymphopoiesis / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D012038:Regeneration / Q000235:genetics; D055153:Stem Cell Niche
D012739:Gonadal Steroid Hormones