Dynamic responses of the haematopoietic stem cell niche to diverse stresses

ABSTRACT Adult haematopoietic stem cells (HSCs) mainly reside in the bone marrow, where stromal and haematopoietic cells regulate their function. The steady state HSC niche has been

extensively studied. In this Review, we focus on how bone marrow microenvironment components respond to different insults including inflammation, malignant haematopoiesis and chemotherapy.

We highlight common and unique patterns among multiple cell types and their environment and discuss current limitations in our understanding of this complex and dynamic tissue. Access

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CHANGE HISTORY * _ 22 JANUARY 2020 A Correction to this paper has been published: https://doi.org/10.1038/s41556-020-0469-0 _ REFERENCES * Ding, L. & Morrison, S. J. Haematopoietic stem

cells and early lymphoid progenitors occupy distinct bone marrow niches. _Nature_ 495, 231–235 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Greenbaum, A. et al. CXCL12 in

early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. _Nature_ 495, 227–230 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bilic-Curcic, I. et

al. Visualizing levels of osteoblast differentiation by a two-color promoter-GFP strategy: type I collagen-GFPcyan and osteocalcin-GFPtpz. _Genesis_ 43, 87–98 (2005). Article  CAS  PubMed 

Google Scholar  * Karsenty, G., Kronenberg, H. M. & Settembre, C. Genetic control of bone formation. _Annu. Rev. Cell Dev. Biol._ 25, 629–648 (2009). Article  CAS  PubMed  Google Scholar

  * Yamazaki, S. et al. Nonmyelinating schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. _Cell_ 147, 1146–1158 (2011). Article  CAS  PubMed  Google Scholar

  * Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. _Nature_ 460, 259–263 (2009). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Ishitobi, H. et al. Flk1-GFP BAC Tg mice: an animal model for the study of blood vessel development. _Exp. Anim._ 59, 615–622 (2010). Article  CAS  PubMed  Google Scholar  *

Claxton, S. et al. Efficient, inducible Cre-recombinase activation in vascular endothelium. _Genesis_ 46, 74–80 (2008). Article  CAS  PubMed  Google Scholar  * Alva, J. A. et al.

VE-Cadherin-Cre-recombinase transgenic mouse: a tool for lineage analysis and gene deletion in endothelial cells. _Dev. Dyn._ 235, 759–767 (2006). Article  CAS  PubMed  Google Scholar  *

Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow.

_Cell Stem Cell_ 15, 154–168 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Joseph, C. et al. Deciphering hematopoietic stem cells in their niches: a critical appraisal of

genetic models, lineage tracing, and imaging strategies. _Cell Stem Cell_ 13, 520–533 (2013). Article  CAS  PubMed  Google Scholar  * Tjin, G. et al. Imaging methods used to study mouse and

human HSC niches: current and emerging technologies. _Bone_ 119, 19–35 (2019). Article  CAS  PubMed  Google Scholar  * Mizoguchi, T. et al. Osterix marks distinct waves of primitive and

definitive stromal progenitors during bone marrow development. _Dev. Cell_ 29, 340–349 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ding, L., Saunders, T. L., Enikolopov,

G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. _Nature_ 481, 457–462 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Liu, Y.

et al. Osterix-cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma. _PLoS One_ 8, e71318 (2013). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. _Nature_ 502, 637–643 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Visnjic,

D. et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. _Blood_ 103, 3258–3264 (2004). Article  CAS  PubMed  Google Scholar  * Strecker, S., Fu, Y., Liu,

Y. & Maye, P. Generation and characterization of _Osterix-_ Cherry reporter mice. _Genesis_ 51, 246–258 (2013). Article  CAS  PubMed  Google Scholar  * Crane, G. M., Jeffery, E. &

Morrison, S. J. Adult haematopoietic stem cell niches. _Nat. Rev. Immunol._ 17, 573–590 (2017). Article  CAS  PubMed  Google Scholar  * Asada, N. et al. Differential cytokine contributions

of perivascular haematopoietic stem cell niches. _Nat. Cell Biol._ 19, 214–223 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yu, V. W. C. & Scadden, D. T. Heterogeneity

of the bone marrow niche. _Curr. Opin. Hematol._ 23, 331–338 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wei, Q. & Frenette, P. S. Niches for hematopoietic stem

cells and their progeny. _Immunity_ 48, 632–648 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Takizawa, H., Boettcher, S. & Manz, M. G. Demand-adapted regulation of

early hematopoiesis in infection and inflammation. _Blood_ 119, 2991–3002 (2012). Article  CAS  PubMed  Google Scholar  * Nagai, Y. et al. Toll-like receptors on hematopoietic progenitor

cells stimulate innate immune system replenishment. _Immunity_ 24, 801–812 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Massberg, S. et al. Immunosurveillance by

hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. _Cell_ 131, 994–1008 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * Baldridge, M.

T., King, K. Y., Boles, N. C., Weksberg, D. C. & Goodell, M. A. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. _Nature_ 465, 793–797

(2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Vainieri, M. L. et al. Systematic tracking of altered haematopoiesis during sporozoite-mediated malaria development reveals

multiple response points. _Open Biol._ 6, 160038 (2016). Article  PubMed  PubMed Central  CAS  Google Scholar  * Matatall, K. A. et al. Chronic infection depletes hematopoietic stem cells

through stress-induced terminal differentiation. _Cell Rep._ 17, 2584–2595 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rashidi, N. M. et al. In vivo time-lapse imaging

shows diverse niche engagement by quiescent and naturally activated hematopoietic stem cells. _Blood_ 124, 79–83 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Boettcher, S.

et al. Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis. _Blood_ 124, 1393–1403 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Khakpour, S., Wilhelmsen, K. & Hellman, J. Vascular endothelial cell Toll-like receptor pathways in sepsis. _Innate Immun._ 21, 827–846 (2015). Article  CAS  PubMed  Google Scholar  *

Prendergast, A. M. et al. IFNα-mediated remodeling of endothelial cells in the bone marrow niche. _Haematologica_ 102, 445–453 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Andonegui, G. et al. Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection. _J. Clin. Invest._ 119, 1921–1930

(2009). CAS  PubMed  PubMed Central  Google Scholar  * Casanova-Acebes, M. et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. _Cell_ 153, 1025–1035 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Shi, C. et al. Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like

receptor ligands. _Immunity_ 34, 590–601 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chou, D. B. et al. Stromal-derived IL-6 alters the balance of myeloerythroid

progenitors during _Toxoplasma gondii_ infection. _J. Leukoc. Biol._ 92, 123–131 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Schurch, C. M., Riether, C. & Ochsenbein,

A. F. Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells. _Cell Stem Cell_ 14, 460–472 (2014). Article  CAS

  PubMed  Google Scholar  * Day, R. B., Bhattacharya, D., Nagasawa, T. & Link, D. C. Granulocyte colony-stimulating factor reprograms bone marrow stromal cells to actively suppress B

lymphopoiesis in mice. _Blood_ 125, 3114–3117 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Schajnovitz, A. et al. CXCL12 secretion by bone marrow stromal cells is

dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. _Nat. Immunol._ 12, 391–398 (2011). Article  CAS  PubMed  Google Scholar  * Petit, I. et al. G-CSF

induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. _Nat. Immunol._ 3, 687–694 (2002). Article  CAS  PubMed  Google Scholar  * Calvi, L. et al.

Osteoblastic cells regulate the haematopoietic stem cell niche. _Nature_ 425, 841–846 (2003). Article  CAS  PubMed  Google Scholar  * Zhang, J. et al. Identification of the haematopoietic

stem cell niche and control of the niche size. _Nature_ 425, 836–841 (2003). Article  CAS  PubMed  Google Scholar  * Terashima, A. et al. Sepsis-induced osteoblast ablation causes

immunodeficiency. _Immunity_ 44, 1434–1443 (2016). Article  CAS  PubMed  Google Scholar  * Imai, T. et al. Cytotoxic activities of CD8+ T cells collaborate with macrophages to protect

against blood-stage murine malaria. _eLife_ 4, e04232 (2015). Article  PubMed Central  Google Scholar  * Joice, R. et al. _Plasmodium falciparum_ transmission stages accumulate in the human

bone marrow. _Sci. Transl. Med._ 6, 244re5 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * Lee, M. S. J. et al. _Plasmodium_ products persist in the bone marrow and promote

chronic bone loss. _Sci. Immunol._ 2, eaam8093 (2017). Article  PubMed  Google Scholar  * McCabe, A. & MacNamara, K. C. Macrophages: key regulators of steady-state and demand-adapted

hematopoiesis. _Exp. Hematol._ 44, 213–222 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Fujisaki, J. et al. In vivo imaging of Treg cells providing immune privilege to the

haematopoietic stem-cell niche. _Nature_ 474, 216–219 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hirata, Y. et al. CD150high bone marrow Tregs maintain hematopoietic

stem cell quiescence and immune privilege via adenosine. _Cell Stem Cell_ 22, 445–453.e5 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Glatman Zaretsky, A. et al. T

regulatory cells support plasma cell populations in the bone marrow. _Cell Reports_ 18, 1906–1916 (2017). Article  CAS  PubMed  Google Scholar  * Chow, A. et al. Bone marrow CD169+

macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. _J. Exp. Med._ 208, 261–271 (2011). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Lieschke, G. J. et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired

neutrophil mobilization. _Blood_ 84, 1737–1746 (1994). Article  CAS  PubMed  Google Scholar  * Schuettpelz, L. G. et al. G-CSF regulates hematopoietic stem cell activity, in part, through

activation of Toll-like receptor signaling. _Leukemia_ 28, 1851–1860 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Westerterp, M. et al. Regulation of hematopoietic stem

and progenitor cell mobilization by cholesterol efflux pathways. _Cell Stem Cell_ 11, 195–206 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Winkler, I. G. et al. Bone

marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. _Blood_ 116, 4815–4828 (2010). Article  CAS  PubMed  Google Scholar  * Gregory, C. D.

& Devitt, A. The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically? _Immunology_ 113, 1–14 (2004). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-γ: an overview of signals, mechanisms and functions. _J. Leukoc. Biol._ 75, 163–189 (2004). Article  CAS 

PubMed  Google Scholar  * McCabe, A. et al. Macrophage-lineage cells negatively regulate the hematopoietic stem cell pool in response to interferon gamma at steady state and during

infection. _Stem Cells_ 33, 2294–2305 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zoller, E. E. et al. Hemophagocytosis causes a consumptive anemia of inflammation. _J.

Exp. Med._ 208, 1203–1214 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Colgan, S. P., Campbell, E. L. & Kominsky, D. J. Hypoxia and mucosal inflammation. _Annu. Rev.

Pathol._ 11, 77–100 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Taylor, C. T. & Colgan, S. P. Regulation of immunity and inflammation by hypoxia in immunological

niches. _Nat. Rev. Immunol._ 17, 774–785 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kwak, H. J. et al. Myeloid cell-derived reactive oxygen species externally regulate

the proliferation of myeloid progenitors in emergency granulopoiesis. _Immunity_ 42, 159–171 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhu, H. et al. Reactive oxygen

species-producing myeloid cells act as a bone marrow niche for sterile inflammation-induced reactive granulopoiesis. _J. Immunol._ 198, 2854–2864 (2017). Article  CAS  PubMed  Google Scholar

  * Kristinsson, S. Y., Landgren, O., Samuelsson, J., Bjorkholm, M. & Goldin, L. R. Autoimmunity and the risk of myeloproliferative neoplasms. _Haematologica_ 95, 1216–1220 (2010).

Article  PubMed  PubMed Central  Google Scholar  * Kristinsson, S. Y. et al. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or

myelodysplastic syndromes. _J. Clin. Oncol._ 29, 2897–2903 (2011). Article  PubMed  PubMed Central  Google Scholar  * Fröhling, S., Scholl, C., Gilliland, D. G. & Levine, R. L. Genetics

of myeloid malignancies: pathogenetic and clinical implications. _J. Clin. Oncol._ 23, 6285–6295 (2005). Article  PubMed  CAS  Google Scholar  * Lane, S. W., Scadden, D. T. & Gilliland,

D. G. The leukemic stem cell niche: Current concepts and therapeutic opportunities. _Blood_ 114, 1150–1157 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang, B. et al.

Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. _Cancer Cell_ 21, 577–592 (2012). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Kode, A. et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. _Nature_ 506, 240–244 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Frisch, B. J. et al. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. _Blood_ 119, 540–550 (2012). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Schepers, K. et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. _Cell Stem Cell_ 13, 285–299 (2013). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Schmidt, T. & Carmeliet, P. Angiogenesis: a target in solid tumors, also in leukemia? _Hematology (Am. Soc. Hematol. Educ. Program)_ 2011, 1–8

(2011). Article  Google Scholar  * Kampen, K. R., Ter Elst, A. & de Bont, E. S. Vascular endothelial growth factor signaling in acute myeloid leukemia. _Cell. Mol. Life Sci._ 70,

1307–1317 (2013). Article  CAS  PubMed  Google Scholar  * Kusumbe, A. P. et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. _Nature_ 532, 380–384 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Itkin, T. et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. _Nature_ 532, 323–328 (2016). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Kusumbe, A. P., Ramasamy, S. K. & Adams, R. H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. _Nature_ 507,

323–328 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Langen, U. H. et al. Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. _Nat. Cell

Biol._ 19, 189–201 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Passaro, D. et al. Increased vascular permeability in the bone marrow microenvironment contributes to

disease progression and drug response in acute myeloid leukemia. _Cancer Cell_ 32, 324–341 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Duarte, D. et al. Inhibition of

endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. _Cell Stem Cell_ 22, 64–77.e6 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Pitt, L. A. et

al. CXCL12-producing vascular endothelial niches control acute T cell leukemia maintenance. _Cancer Cell_ 27, 755–768 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Passaro,

D. et al. CXCR4 is required for leukemia-initiating cell activity in T cell acute lymphoblastic leukemia. _Cancer Cell_ 27, 769–779 (2015). Article  CAS  PubMed  Google Scholar  * Duarte,

D. et al. Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging. _Immunol. Cell Biol._ 97, 229–235 (2019). Article  PubMed  Google Scholar  *

Goulard, M., Dosquet, C. & Bonnet, D. Role of the microenvironment in myeloid malignancies. _Cell. Mol. Life Sci._ 75, 1377–1391 (2018). Article  CAS  PubMed  Google Scholar  * Dominici,

M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. _Cytotherapy_ 8, 315–317 (2006). Article 

CAS  PubMed  Google Scholar  * Geyh, S. et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. _Leukemia_ 27, 1841–1851

(2013). Article  CAS  PubMed  Google Scholar  * von der Heide, E. K., Neumann, M. & Baldus, C. D. Targeting the leukemic bone marrow microenvironment. _Oncotarget_ 8, 96474–96475 (2017).

Article  PubMed  PubMed Central  Google Scholar  * Baryawno, N. et al. A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia. _Cell_ 177, 1915–1932.e16 (2019). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Manshouri, T. et al. Bone marrow stroma-secreted cytokines protect JAK2V617F-mutated cells from the effects of a JAK2 inhibitor. _Cancer Res._

71, 3831–3840 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Guarnerio, J. et al. A non-cell-autonomous role for Pml in the maintenance of leukemia from the niche. _Nat.

Commun._ 9, 66 (2018). Article  PubMed  PubMed Central  CAS  Google Scholar  * Dong, L. et al. Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment.

_Nature_ 539, 304–308 (2016). Article  PubMed  PubMed Central  CAS  Google Scholar  * Vianello, F. et al. Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid

leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis. _Haematologica_ 95, 1081–1089 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tavor, S. et al. CXCR4

regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. _Cancer Res._ 64, 2817–2824 (2004). Article  CAS  PubMed  Google Scholar  *

Hawkins, E. D. et al. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. _Nature_ 538, 518–522 (2016). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Battula, V. L. et al. AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth. _JCI Insight_ 2, e90036 (2017). Article  PubMed Central  Google

Scholar  * Schepers, K. et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. _Cell Stem Cell_ 13, 285–299 (2013). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Raaijmakers, M. H. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. _Nature_ 464, 852–857 (2010). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Tabe, Y. et al. Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of

acute monocytic leukemia cells. _Cancer Res._ 77, 1453–1464 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shafat, M. S., Gnaneswaran, B., Bowles, K. M. & Rushworth, S.

A. The bone marrow microenvironment - home of the leukemic blasts. _Blood Rev._ 31, 277–286 (2017). Article  PubMed  Google Scholar  * Cahu, X. et al. Bone marrow sites differently imprint

dormancy and chemoresistance to T-cell acute lymphoblastic leukemia. _Blood Adv._ 1, 1760–1772 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Behan, J. W. et al. Adipocytes

impair leukemia treatment in mice. _Cancer Res._ 69, 7867–7874 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Asano, J. et al. The serine/threonine kinase Pim-2 is a novel

anti-apoptotic mediator in myeloma cells. _Leukemia_ 25, 1182–1188 (2011). Article  CAS  PubMed  Google Scholar  * Decker, S. et al. PIM kinases are essential for chronic lymphocytic

leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). _Mol. Cancer Ther._ 13, 1231–1245 (2014). Article  CAS  PubMed  Google Scholar  * Ruan, J. et al.

Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease. _Bone_ 57, 10–17 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Boyd, A. L. et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. _Nat. Cell Biol._ 19, 1336–1347 (2017). Article  CAS 

PubMed  Google Scholar  * Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. _Nature_ 466, 829–834 (2010). Article  PubMed  PubMed Central 

CAS  Google Scholar  * Arranz, L. et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. _Nature_ 512, 78–81 (2014). Article  CAS  PubMed  Google

Scholar  * Giannopoulos, K. et al. Characterization of regulatory T cells in patients with B-cell chronic lymphocytic leukemia. _Oncol. Rep._ 20, 677–682 (2008). PubMed  Google Scholar  *

Muthu Raja, K. R. et al. Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma. _PLoS One_ 7, e47077 (2012). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Mansour, I., Zayed, R. A., Said, F. & Latif, L. A. Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia. _Hematology_

21, 447–453 (2016). Article  CAS  PubMed  Google Scholar  * Kawano, Y. et al. Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression. _J. Clin. Invest._ 128,

2487–2499 (2018). Article  PubMed  PubMed Central  Google Scholar  * Molldrem, J. J. et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous

leukemia. _Nat. Med._ 6, 1018–1023 (2000). Article  CAS  PubMed  Google Scholar  * Butt, N. M. et al. Circulating bcr-abl-specific CD8+ T cells in chronic myeloid leukemia patients and

healthy subjects. _Haematologica_ 90, 1315–1323 (2005). CAS  PubMed  Google Scholar  * Schurch, C., Riether, C., Amrein, M. A. & Ochsenbein, A. F. Cytotoxic T cells induce proliferation

of chronic myeloid leukemia stem cells by secreting interferon-gamma. _J. Exp. Med._ 210, 605–621 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yang, L. et al. IFN-γ

negatively modulates self-renewal of repopulating human hemopoietic stem cells. _J. Immunol._ 174, 752–757 (2005). Article  CAS  PubMed  Google Scholar  * Gabrilovich, D. I. & Nagaraj,

S. Myeloid-derived suppressor cells as regulators of the immune system. _Nat. Rev. Immunol._ 9, 162–174 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen, X. et al.

Induction of myelodysplasia by myeloid-derived suppressor cells. _J. Clin. Invest._ 123, 4595–4611 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Van Valckenborgh, E. et al.

Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow. _Leukemia_ 26, 2424–2428 (2012). Article  PubMed 

Google Scholar  * Giallongo, C. et al. Myeloid derived suppressor cells (MDSCs) are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs) in

chronic myeloid leukemia patients. _PLoS One_ 9, e101848 (2014). Article  PubMed  PubMed Central  Google Scholar  * Jitschin, R. et al. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived

suppressor cells that inhibit T-cell responses and promote TRegs. _Blood_ 124, 750–760 (2014). Article  CAS  PubMed  Google Scholar  * Giallongo, C. et al. Mesenchymal stem cells (MSC)

regulate activation of granulocyte-like myeloid derived suppressor cells (G-MDSC) in chronic myeloid leukemia patients. _PLoS One_ 11, e0158392 (2016). Article  PubMed  PubMed Central  CAS 

Google Scholar  * Giallongo, C. et al. Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells

(MSC). _Oncotarget_ 7, 85764–85775 (2016). Article  PubMed  PubMed Central  Google Scholar  * Pyzer, A. R. et al. MUC1-mediated induction of myeloid-derived suppressor cells in patients with

acute myeloid leukemia. _Blood_ 129, 1791–1801 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Serafini, P., Mgebroff, S., Noonan, K. & Borrello, I. Myeloid-derived

suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. _Cancer Res._ 68, 5439–5449 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hay,

N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? _Nat. Rev. Cancer_ 16, 635–649 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Valsecchi, R. et al. HIF-1alpha regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment. _Blood_ 127, 1987–1997 (2016). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Benito, J. et al. Hypoxia-activated prodrug TH-302 targets hypoxic bone marrow niches in preclinical leukemia models. _Clin. Cancer Res._ 22, 1687–1698 (2016).

Article  CAS  PubMed  Google Scholar  * Das, D. S. et al. A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells.

_Leukemia_ 30, 2187–2197 (2016). Article  PubMed  PubMed Central  CAS  Google Scholar  * Moschoi, R. et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid

leukemic cells during chemotherapy. _Blood_ 128, 253–264 (2016). Article  CAS  PubMed  Google Scholar  * Liu, J. et al. Stromal cell-mediated mitochondrial redox adaptation regulates drug

resistance in childhood acute lymphoblastic leukemia. _Oncotarget_ 6, 43048–43064 (2015). Article  PubMed  PubMed Central  Google Scholar  * Zhang, W. et al. Stromal control of cystine

metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. _Nat. Cell Biol._ 14, 276–286 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lagadinou, E. D. et

al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. _Cell Stem Cell_ 12, 329–341 (2013). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Cole, A. et al. Inhibition of the mitochondrial protease ClpP as a therapeutic strategy for human acute myeloid leukemia. _Cancer Cell_ 27, 864–876 (2015). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Rodriguez, A. M., Nakhle, J., Griessinger, E. & Vignais, M. L. Intercellular mitochondria trafficking highlighting the dual role of

mesenchymal stem cells as both sensors and rescuers of tissue injury. _Cell Cycle_ 17, 712–721 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Marlein, C. R. et al. NADPH

oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. _Blood_ 130, 1649–1660 (2017). Article  CAS  PubMed  Google Scholar  *

Ricciardi, M. R. et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. _Blood_ 126, 1925–1929 (2015). Article  CAS  PubMed 

Google Scholar  * Ye, H. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. _Cell Stem Cell_ 19, 23–37 (2016). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Ehsanipour, E. A. et al. Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine. _Cancer Res._ 73, 2998–3006 (2013). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Kalaitzidis, D. et al. Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. _J. Clin.

Invest._ 127, 1405–1413 (2017). Article  PubMed  PubMed Central  Google Scholar  * Lazare, S. et al. Lifelong dietary intervention does not affect hematopoietic stem cell function. _Exp.

Hematol._ 53, 26–30 (2017). Article  PubMed  Google Scholar  * Lu, Z. et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. _Nat.

Med._ 23, 79–90 (2017). Article  CAS  PubMed  Google Scholar  * Ghosh, J. & Kapur, R. Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid

leukemia. _Exp. Hematol._ 50, 13–21 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Agathocleous, M. et al. Ascorbate regulates haematopoietic stem cell function and

leukaemogenesis. _Nature_ 549, 476–481 (2017). Article  PubMed  PubMed Central  Google Scholar  * Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia

progression. _Cell_ 170, 1079–1095.e20 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wood, M. E. et al. Second malignant neoplasms: assessment and strategies for risk

reduction. _J. Clin. Oncol._ 30, 3734–3745 (2012). Article  PubMed  Google Scholar  * Green, D. E. & Rubin, C. T. Consequences of irradiation on bone and marrow phenotypes, and its

relation to disruption of hematopoietic precursors. _Bone_ 63, 87–94 (2014). Article  CAS  PubMed  Google Scholar  * Kondo, H. et al. Total-body irradiation of postpubertal mice with 137 Cs

acutely compromises the microarchitecture of cancellous bone and increases osteoclasts. _Radiat. Res._ 171, 283–289 (2009). Article  CAS  PubMed  Google Scholar  * Willey, J. S. et al. Early

increase in osteoclast number in mice after whole-body irradiation with 2 Gy X rays. _Radiat. Res._ 170, 388–392 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Mauch, P. et

al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. _Int. J. Radiat. Oncol. Biol. Phys._ 31, 1319–1339 (1995). Article  CAS  PubMed 

Google Scholar  * Gong, B., Oest, M. E., Mann, K. A., Damron, T. A. & Morris, M. D. Raman spectroscopy demonstrates prolonged alteration of bone chemical composition following extremity

localized irradiation. _Bone_ 57, 252–258 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rieger, K. et al. Mesenchymal stem cells remain of host origin even a long time

after allogeneic peripheral blood stem cell or bone marrow transplantation. _Exp. Hematol._ 33, 605–611 (2005). Article  CAS  PubMed  Google Scholar  * Dickhut, A. et al. Mesenchymal stem

cells obtained after bone marrow transplantation or peripheral blood stem cell transplantation originate from host tissue. _Ann. Hematol._ 84, 722–727 (2005). Article  PubMed  Google Scholar

  * Abbuehl, J.-P., Tatarova, Z., Held, W. & Huelsken, J. Long-term engraftment of primary bone marrow stromal cells repairs niche damage and improves hematopoietic stem cell

transplantation. _Cell Stem Cell_ 21, 241–255.e6 (2017). Article  CAS  PubMed  Google Scholar  * Cao, X. et al. Irradiation induces bone injury by damaging bone marrow microenvironment for

stem cells. _Proc. Natl. Acad. Sci. USA_ 108, 1609–1614 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhou, B. O. et al. Bone marrow adipocytes promote the regeneration of

stem cells and haematopoiesis by secreting SCF. _Nat. Cell Biol._ 19, 891–903 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hooper, A. T. et al. Engraftment and

reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. _Cell Stem Cell_ 4, 263–274 (2009). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Poulos, M. G. et al. Endothelial jagged-1 is necessary for homeostatic and regenerative hematopoiesis. _Cell Rep._ 4, 1022–1034 (2013). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Bowers, E. et al. Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow. _Nat. Med._ 24, 95–102 (2018). Article  CAS  PubMed  Google

Scholar  * Kaur, S. et al. Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment. _Blood_ 132, 735–749 (2018). Article  CAS 

PubMed  Google Scholar  * Gencheva, M. et al. Bone marrow osteoblast vulnerability to chemotherapy. _Eur. J. Haematol._ 90, 469–478 (2013). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Tikhonova, A. N. et al. The bone marrow microenvironment at single-cell resolution. _Nature_ 569, 222–228 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Itkin, T.

et al. FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation. _Blood_ 120, 1843–1855 (2012). Article

  CAS  PubMed  Google Scholar  * Zhao, M. et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. _Nat. Med._ 20, 1321–1326

(2014). Article  CAS  PubMed  Google Scholar  * Hérault, A. et al. Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis. _Nature_ 544, 53–58 (2017). Article 

PubMed  PubMed Central  CAS  Google Scholar  * Lucas, D. et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. _Nat. Med._ 19, 695–703 (2013). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Palen, K., Thakar, M., Johnson, B. D. & Gershan, J. A. Bone marrow-derived CD8+ T cells from pediatric leukemia patients express PD1 and

expand ex vivo following induction chemotherapy. _J. Pediatr. Hematol. Oncol._ 41, 648–652 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wemeau, M. et al. Calreticulin

exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia. _Cell Death Dis._ 1, e104 (2010). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Fucikova, J. et al. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. _Cancer Res._ 71, 4821–4833 (2011). Article  CAS  PubMed  Google

Scholar  * Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. _Science_ 334, 1573–1577 (2011). Article  CAS  PubMed  Google

Scholar  * Ersvaer, E., Liseth, K., Skavland, J., Gjertsen, B. T. & Bruserud, O. Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and

TREG cells. _BMC Immunol._ 11, 38 (2010). Article  PubMed  PubMed Central  CAS  Google Scholar  * Salem, M. L. et al. Chemotherapy alters the increased numbers of myeloid-derived suppressor

and regulatory T cells in children with acute lymphoblastic leukemia. _Immunopharmacol. Immunotoxicol._ 40, 158–167 (2018). Article  CAS  PubMed  Google Scholar  * Barrett, D. M., Teachey,

D. T. & Grupp, S. A. Toxicity management for patients receiving novel T-cell engaging therapies. _Curr. Opin. Pediatr._ 26, 43–49 (2014). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. _N. Engl. J. Med._ 368, 1509–1518 (2013). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. _N. Engl. J. Med._ 371, 1507–1517 (2014). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. _Nat. Med._ 24, 731–738 (2018). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Coutu, D. L., Kokkaliaris, K. D., Kunz, L. & Schroeder, T. Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules. _Nat.

Biotechnol._ 35, 1202–1210 (2017). Article  CAS  PubMed  Google Scholar  * Gligorijevic, B. et al. Intravital imaging and photoswitching in tumor invasion and intravasation

microenvironments. _Micros. Today_ 18, 34–37 (2010). Article  PubMed  PubMed Central  Google Scholar  * Carlson, A. L. et al. Tracking single cells in live animals using a photoconvertible

near-infrared cell membrane label. _PLoS One_ 8, e69257 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Turcotte, R., Wu, J. W. & Lin, C. P. Intravital multiphoton

photoconversion with a cell membrane dye. _J. Biophotonics_ 10, 206–210 (2017). Article  CAS  PubMed  Google Scholar  * Alieva, M., Ritsma, L., Giedt, R. J., Weissleder, R. & van

Rheenen, J. Imaging windows for long-term intravital imaging: general overview and technical insights. _Intravital_ 3, e29917 (2014). Article  PubMed  PubMed Central  Google Scholar 

Download references ACKNOWLEDGEMENTS This Review was supported in parts by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001045), the UK Medical

Research Council (FC001045) and the Wellcome Trust (FC001045) to D.B. and by grants from the European Research Council (ERC STG 337066), the British Biology and Biotechnology Research

council (BB/i004033/1) and Bloodwise (15031 and 15040), Cancer Research UK (C36195/A26770) and the Wellcome Trust (212304/Z/18/Z) to C.L.C. A.B. and D.P. are recipients of the Junior EHA

fellowship. M.L.R.H. was funded by the Wellcome Trust. AUTHOR INFORMATION Author notes * These authors contributed equally: Antoniana Batsivari, Myriam Luydmila Rachelle Haltalli, Diana

Passaro, Constandina Pospori. AUTHORS AND AFFILIATIONS * Haematopoietic Stem Cell Laboratory, The Francis Crick Institute , London, UK Antoniana Batsivari, Diana Passaro, Constandina

Pospori, Cristina Lo Celso & Dominique Bonnet * Department of Life Sciences, Imperial College London, South Kensington campus, London, UK Myriam Luydmila Rachelle Haltalli, Constandina

Pospori & Cristina Lo Celso * Lo Celso Laboratory, The Francis Crick Institute, London, UK Myriam Luydmila Rachelle Haltalli, Constandina Pospori & Cristina Lo Celso Authors *

Antoniana Batsivari View author publications You can also search for this author inPubMed Google Scholar * Myriam Luydmila Rachelle Haltalli View author publications You can also search for

this author inPubMed Google Scholar * Diana Passaro View author publications You can also search for this author inPubMed Google Scholar * Constandina Pospori View author publications You

can also search for this author inPubMed Google Scholar * Cristina Lo Celso View author publications You can also search for this author inPubMed Google Scholar * Dominique Bonnet View

author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Cristina Lo Celso or Dominique Bonnet. ETHICS DECLARATIONS COMPETING

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institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Batsivari, A., Haltalli, M.L.R., Passaro, D. _et al._ Dynamic responses of

the haematopoietic stem cell niche to diverse stresses. _Nat Cell Biol_ 22, 7–17 (2020). https://doi.org/10.1038/s41556-019-0444-9 Download citation * Received: 28 August 2018 * Accepted: 27

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