The bone marrow niche landscape: a journey through aging, extrinsic and intrinsic stressors in the haemopoietic milieu

Abstract

Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems, thought to properly sustain blood cell production and distinguish between friend and foe, can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state. The bone marrow niche hijacks the physiologic hematopoiesis. The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence. We examined several approaches to confront the available evidence; three key points emerged, pointing to the chronic inflammation process, especially the chronic infection and systemic inflammatory states, as leading causes of hematopoietic stem cell depletion. Clonal hematopoiesis, defined as a relative expansion of individual clones, is caused by somatic alterations in essential hematopoietic genes, which increase stem cell fitness. Moreover, terminal differentiation plays a significant role in progenitor loss and inflammatory signaling, promoting clonal selection and clonal hematopoiesis conditions. Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation, including the 5q- syndrome, Philadelphia negative myeloproliferative neoplasms, and chronic myeloid leukemia. Aging with increased fitness and hematopoietic stem cell attrition, extrinsic stress, enhanced stressor-specific fitness, and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis. The discussion in this review also points out that the hematopoietic niches’ inflammatory stimulation may affect differentiation patterns and the function of downstream cells.

Keywords

Hematopoietic niche / immune system / inflammation / tumor microenvironment

References

[1] Gleitz HF,Schneider RK.Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis.J Pathol2018;245:138-46 PMCID:PMC5969225

[2] Calvi LM,Weibrecht KW.Osteoblastic cells regulate the haematopoietic stem cell niche.Nature2003;425:841-6

[3] Davies JM,Begun J,Winkler IG.Adhesion to E-selectin primes macrophages for activation through AKT and mTOR.Immunol Cell Biol2021;99:622-39

[4] Solimando AG,Vacca A.Cancer-associated angiogenesis: the endothelial cell as a checkpoint for immunological patrolling.Cancers (Basel)2020;12:3380 PMCID:PMC7696032

[5] Wilson A.Bone-marrow haematopoietic-stem-cell niches.Nat Rev Immunol2006;6:93-106

[6] El Agha E,Schneider RK.Mesenchymal stem cells in fibrotic disease.Cell Stem Cell2017;21:166-77

[7] Chasis JA.Erythroblastic islands: niches for erythropoiesis.Blood2008;112:470-8 PMCID:PMC2481536

[8] Kovtonyuk LV,Feng X,Takizawa H.Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment.Front Immunol2016;7:502 PMCID:PMC5107568

[9] Kennedy DE.Inflammatory changes in bone marrow microenvironment associated with declining B lymphopoiesis.J Immunol2017;198:3471-9 PMCID:PMC5435233

[10] Griffith JF.Age-related changes in the bone marrow.Curr Radiol Rep2017;5:24

[11] Vleeming W,Wemer J.Cardiovascular responses to the stereoisomers of dobutamine in isolated rat hearts 48 hours after acute myocardial infarction.J Cardiovasc Pharmacol1991;17:634-40

[12] Ambrosi TH,Graja A.Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.Cell Stem Cell2017;20:771-84.e6 PMCID:PMC5459794

[13] Pietras EM.Inflammation: a key regulator of hematopoietic stem cell fate in health and disease.Blood2017;130:1693-8 PMCID:PMC5639485

[14] Reynaud D,Barry-Holson K.IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development.Cancer Cell2011;20:661-73 PMCID:PMC3220886

[15] Gondek LP.CHIP: is clonal hematopoiesis a surrogate for aging and other disease?.Hematology Am Soc Hematol Educ Program2021;2021:384-9 PMCID:PMC8791098

[16] Tomasetti C.Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.Science2015;347:78-81 PMCID:PMC4446723

[17] Jaiswal S.Clonal hematopoiesis in human aging and disease.Science2019;366:eaan4673 PMCID:PMC8050831

[18] Young AL,Birmann BM.Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults.Nat Commun2016;7:12484 PMCID:PMC4996934

[19] Zink F,Norddahl GL.Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.Blood2017;130:742-52 PMCID:PMC5553576

[20] Genovese G,Handsaker RE.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med2014;371:2477-87 PMCID:PMC4290021

[21] Jaiswal S,Flannick J.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med2014;371:2488-98 PMCID:PMC4306669

[22] Coombs CC,Devlin SM.Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes.Cell Stem Cell2017;21:374-382.e4 PMCID:PMC5591073

[23] Gnoni A,Longo V.Immune system and bone microenvironment: rationale for targeted cancer therapies.Oncotarget2020;11:480-7 PMCID:PMC6996902

[24] Elias HK,Park CY.Molecular mechanisms underlying lineage bias in aging hematopoiesis.Semin Hematol2017;54:4-11

[25] Watson CJ,Poon GYP.The evolutionary dynamics and fitness landscape of clonal hematopoiesis.Science2020;367:1449-54

[26] Gibson CJ,Zhao L.Donor clonal hematopoiesis and recipient outcomes after transplantation.J Clin Oncol2022;40:189-201 PMCID:PMC8718176

[27] Bolton KL,Gao T.Cancer therapy shapes the fitness landscape of clonal hematopoiesis.Nat Genet2020;52:1219-26 PMCID:PMC7891089

[28] Wong TN,Young AL.Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.Nature2015;518:552-5 PMCID:PMC4403236

[29] McNerney ME,Le Beau MM.Therapy-related myeloid neoplasms: when genetics and environment collide.Nat Rev Cancer2017;17:513-27 PMCID:PMC5946699

[30] Yoshizato T,Hosokawa K.Somatic mutations and clonal hematopoiesis in aplastic anemia.N Engl J Med2015;373:35-47 PMCID:PMC7478337

[31] Sun L.Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria.Blood2020;136:36-49 PMCID:PMC7332901

[32] Jaiswal S.Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease.Nat Rev Cardiol2020;17:137-44

[33] Jaiswal S,Silver AJ.Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease.N Engl J Med2017;377:111-21 PMCID:PMC6717509

[34] Fuster JJ,Zuriaga MA.Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.Science2017;355:842-7 PMCID:PMC5542057

[35] Wolach O,Martinod K.Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms.Sci Transl Med2018;10:eaan8292 PMCID:PMC6442466

[36] Furman D,Verdin E.Chronic inflammation in the etiology of disease across the life span.Nat Med2019;25:1822-32 PMCID:PMC7147972

[37] Fraenkel PG.Anemia of inflammation: a review.Med Clin North Am2017;101:285-96 PMCID:PMC5308549

[38] Bruin AM, Voermans C, Nolte MA. Impact of interferon-γ on hematopoiesis.Blood2014;124:2479-86

[39] Zamai L,Pierpaoli S.TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis.Blood2000;95:3716-24

[40] Baldridge MT,Boles NC,Goodell MA.Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection.Nature2010;465:793-7 PMCID:PMC2935898

[41] Essers MA,Blanco-Bose WE.IFNalpha activates dormant haematopoietic stem cells in vivo.Nature2009;458:904-8

[42] Esplin BL,Welner RS.Chronic exposure to a TLR ligand injures hematopoietic stem cells.J Immunol2011;186:5367-75 PMCID:PMC3086167

[43] Pietras EM,Fong S.Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.Nat Cell Biol2016;18:607-18 PMCID:PMC4884136

[44] Ruchala P.The pathophysiology and pharmacology of hepcidin.Trends Pharmacol Sci2014;35:155-61 PMCID:PMC3978192

[45] Ganz T.Hepcidin and disorders of iron metabolism.Annu Rev Med2011;62:347-60

[46] Keel SB.The microcytic red cell and the anemia of inflammation.N Engl J Med2009;361:1904-6 PMCID:PMC3741048

[47] Hom J,Mohandas N.The erythroblastic island as an emerging paradigm in the anemia of inflammation.Immunol Res2015;63:75-89 PMCID:PMC4651743

[48] Barreyro L,Starczynowski DT.Chronic immune response dysregulation in MDS pathogenesis.Blood2018;132:1553-60 PMCID:PMC6182269

[49] Matatall KA,Chen S.Chronic infection depletes hematopoietic stem cells through stress-induced terminal differentiation.Cell Rep2016;17:2584-95 PMCID:PMC5161248

[50] Florez MA,Jeong Y.Interferon gamma mediates hematopoietic stem cell activation and niche relocalization through BST2.Cell Rep2020;33:108530 PMCID:PMC7816211

[51] Schneider RK,Ferreira MV.Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9.Nat Med2016;22:288-97 PMCID:PMC4870050

[52] Ribezzo F,Ziegler S.Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome.Leukemia2019;33:1759-72

[53] Zambetti NA,Chen S.Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia.Cell Stem Cell2016;19:613-27

[54] Sallman DA,Basiorka AA.Unraveling the pathogenesis of MDS: the NLRP3 inflammasome and pyroptosis drive the MDS phenotype.Front Oncol2016;6:151 PMCID:PMC4909736

[55] Arranz L,Martín-Pérez D.Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.Nature2014;512:78-81

[56] Decker M,Wang G.Leptin-receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis.Nat Cell Biol2017;19:677-88 PMCID:PMC5801040

[57] Hanoun M,Mizoguchi T.Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche.Cell Stem Cell2014;15:365-75 PMCID:PMC4156919

[58] Meisel M,Pacis A.Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host.Nature2018;557:580-4 PMCID:PMC6238954

[59] Schepers K,Reynaud D.Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche.Cell Stem Cell2013;13:285-99 PMCID:PMC3769504

[60] Kaufmann E,Dunn JL.BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis.Cell2018;172:176-90.e19

[61] Steer K,Morris M.Bone health in patients with hematopoietic disorders of bone marrow origin: systematic review and meta-analysis.J Bone Miner Res2017;32:731-42

[62] Kramann R,DiRocco DP.Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.Cell Stem Cell2015;16:51-66 PMCID:PMC4289444

[63] Schneider RK,Dugourd A.Gli1⁺ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target.Cell Stem Cell2017;20:785-800.e8 PMCID:PMC6485654

[64] Leimkühler NB,Ronghui L.Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.Cell Stem Cell2021;28:637-52.e8 PMCID:PMC8024900

[65] Pellagatti A,Giagounidis A.Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes.Br J Haematol2008;142:57-64 PMCID:PMC2440427

[66] Kovačić M,Beleslin-Čokić B.TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms.Cell Oncol (Dordr)2018;41:541-53

[67] Nemeth E,Gabayan V.IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.J Clin Invest2004;113:1271-6 PMCID:PMC398432

[68] Koschmieder S,Hasselbalch HC.Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both.Leukemia2016;30:1018-24

[69] Galán-Díez M,Kousteni S.The bone marrow microenvironment in health and myeloid malignancy.Cold Spring Harb Perspect Med2018;8:a031328 PMCID:PMC6027930

[70] Lamanuzzi A,Desantis V.Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma.Oncotarget2018;9:20563-77 PMCID:PMC5945497

[71] Girelli D,Swinkels DW.Hepcidin in the diagnosis of iron disorders.Blood2016;127:2809-13 PMCID:PMC4956612

[72] Lorenz L,Poets CF.A review of cord blood concentrations of iron status parameters to define reference ranges for preterm infants.Neonatology2013;104:194-202

[73] Goodnough LT.Evaluation and management of anemia in the elderly.Am J Hematol2014;89:88-96 PMCID:PMC4289144

[74] Ganz T.Anemia of inflammation.N Engl J Med2019;381:1148-57

[75] Frodermann V,Courties G.Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells.Nat Med2019;25:1761-71 PMCID:PMC6858591

[76] Revy P,Fischer A.Somatic genetic rescue in Mendelian haematopoietic diseases.Nat Rev Genet2019;20:582-98

[77] Pasca S.Clonal hematopoiesis and bone marrow failure syndromes.Best Pract Res Clin Haematol2021;34:101273 PMCID:PMC8374084

[78] Germeshausen M,Welte K.Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey.Blood2007;109:93-9

[79] Leone P,Malerba E.Actors on the scene: immune cells in the myeloma niche.Front Oncol2020;10:599098 PMCID:PMC7658648

[80] Sugiyama T.Bone marrow niches for hematopoietic stem cells and immune cells.Inflamm Allergy Drug Targets2012;11:201-6 PMCID:PMC3405285

[81] Hosokawa K,Yoshihara H.Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction.Biochem Biophys Res Commun2007;363:578-83

[82] Solimando AG,Leone P.Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression.Haematologica2021;106:1943-56 PMCID:PMC8252928

[83] Saltarella I,Melaccio A.Mechanisms of resistance to anti-CD38 daratumumab in multiple myeloma.Cells2020;9:167-80 PMCID:PMC7017193

[84] Solimando AG,Vacca A.Targeting B-cell non Hodgkin lymphoma: new and old tricks.Leuk Res2016;42:93-104

[85] Chien KS,Nogueras-Gonzalez GM.Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.Br J Haematol2021;195:378-87