Life science
Medicine, Cellular medicine

How bone marrow regenerates after chemotherapy
Department of Immunology and Cell Biology, Graduate School of Frontier Biosciences / Graduate School of Medicine
Professor Masaru Ishii

Researchmap https://researchmap.jp/read0076684?lang=en

Department of Hematology and Oncology, Graduate School of Medicine
Assistant Professor Takao Sudo

Researchmap https://researchmap.jp/kik?lang=en

Life science

Abstract
Chemotherapy has a damaging effect on hematopoietic stemand progenitor cells (HSPCs) in bone marrow. However, once
chemotherapy ends, HSPCs regenerate, a process that has remained unknown. In this study, we show that BM-resident group
2 innate lymphoid cells (ILC2s) support the recovery of HSPCs
from chemotherapy-induced stress by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF). Mechanistically, IL33 released from chemo-sensitive B cell progenitors activates
MyD88-mediated secretion of GM-CSF in ILC2. GM-CSF knockout mice showed severe loss of myeloid lineage cells following
chemotherapy, causing lethality, which was rescued by transferring
BM ILC2s from wild-type mice. Further, the adoptive transfer ofILC2s accelerates hematopoietic recovery. ILC2s may function by"sensing" the damaged BM spaces and subsequently support hematopoietic recovery under stress conditions. Thus, we clarify theessential mechanism of hematopoietic recovery after bone marrow
injury.

▍ Background & Results
The cell-cycle status of hematopoietic stem and progenitor cells(HSPCs) becomes activated following chemotherapy-induced
stress, promoting bone marrow (BM) regeneration; however, theunderlying molecular mechanism remains elusive. Our goal is toelucidate the key signals transmitted from stressed BM environments. To achieve this, we conducted a comprehensive RNAseq analysis of transplanted HSPCs that had homed into recipient
BM treated with or without an anti-cancer drug 5-fluorouracil (5FU). Upstream analysis revealed that signals from colony-stimulating factor 2 (GM-CSF) were activated in HSPCs transplanted
into 5-FU-treated mice. GM-CSF-deficient mice treated with 5-FU
showed severe loss of myeloid lineage cells, suggested that GMCSF is crucial for BM recovery. Single cell RNA-seq analysis of BMcells from 5-FU-treated mice revealed that group 2 innate lymphoidcells (ILC2s) expressed high level of GM-CSF. Nevertheless, theexpression level was dramatically suppressed in BM ILC2s obtained from 5-FU-treated MyD88- or IL-33-deficient mice comparedto those from wild-type mice. These results suggested that IL-33
activates MyD88-mediated secretion of GM-CSF in ILC2. Further,
the adoptive transfer of ILC2s to 5-FU-treated mice accelerated
hematopoietic recovery. These results indicated that BM-resident
ILC2s support the recovery of HSPCs from 5-FU-induced stress bysecreting GM-CSF.

ation, meaning that it might have therapeutic potential in myelosuppressive conditions. An improved understanding of how GM-CSF
and other growth factors modulate the balance between self-renewal and differentiation of HSPCs in stressed microenvironment
will provide clues for better adjunct therapy aimed at early hematopoietic recovery and for the development of ex vivo expansion ofhematopoietic stem cells.

Figure1
Single-cell RNA-seq analysis of bone marrow showing that GM-CSF-positive cluster is composed of ILC2s.

Figure2
Adoptive transfer of ILC2s resulted in the improved survival of GM-CSF-KO mice
after treatment with 5-FU.

▍ Significance of the research and Future perspective
In this study, we address a fundamental question regarding thetrigger of hematopoietic recovery at an early time point in bonemarrow injury. Our findings show that the adoptive transfer of ILC2s
resulted in faster recovery during the process of myeloid differenti-Figure3
After chemotherapy, bone marrow-resident ILC2s receive cytokine signals fromdying cells and support hematopoietic recovery through secretion of GM-CSF.

P a t e n tSudo, T; Ishii, M et al. Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions. J Exp Med. 2021; 218(5): e20200817. doi:10.1084/jem.20200817.
UR
L http://www.icb.med.osaka-u.ac.jp/index.html
K e y w o r d GM-CSF, group 2 innate lymphoid cell, in vivo imaging
Tr e a t i s e