Abstract
Adult hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and provide the basis to fulfill the hematopoietic needs of an organism. Their properties of self-renewal and multilineage differentiation are controlled by direct interaction with a specific microenvironment – the so-called stem cell ‘niche’. Conceptual advances in our understanding of the composition of the HSC compartment suggest that changes in the BM HSC microenvironment may reflect the aging process. The balance and extent of the effect of intrinsic versus extrinsic (environment) changes during aging on HSC are still under investigation. Growing evidence suggests that the BM HSC niche is very important in the regulation of cellular aging of HSCs. A young HSC niche would act as a protective environment, preventing HSC DNA damage, as well as replicative senescence through protection from radicals and toxic compounds, and prevention/amelioration of aging-associated signaling pathways resulting in epigenetic/genetic modifications, hematopoietic impairments, and cancer predisposition. To what extent the aging of the niche contributes to the “HSC aging” phenotype remains unknown. The analysis of the effect of aging on the activity of these specialized cell “niches” and their molecular products is the focus of this chapter.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Allsopp RC, Morin GB et al (2003) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102(2):517–520
Ara T, Tokoyoda K et al (2003) Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 19(2):257–267
Arai F, Suda T (2007) Regulation of hematopoietic stem cells in the osteoblastic niche. Adv Exp Med Biol 602:61–67
Avigdor A, Goichberg P et al (2004) CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 103(8):2981–2989
Baraibar MA, Friguet B (2013) Oxidative proteome modifications target specific cellular pathways during oxidative stress, cellular senescence and aging. Exp Gerontol 48(7):620–625
Calvi LM, Adams GB et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846
Cancelas JA, Koevoet WL et al (2000) Connexin-43 gap junctions are involved in multiconnexin-expressing stromal support of hemopoietic progenitors and stem cells. Blood 96(2):498–505
Cao JJ, Kurimoto P et al (2007) Aging impairs IGF-I receptor activation and induces skeletal resistance to IGF-I. J Bone Miner Res 22(8):1271–1279
Casanova-Acebes M, Pitaval C et al (2013) Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell 153(5):1025–1035
Chambers SM, Shaw CA et al (2007) Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5(8), e201
Chitteti BR, Cheng YH et al (2013) Hierarchical organization of osteoblasts reveals the significant role of CD166 in hematopoietic stem cell maintenance and function. Bone 54(1):58–67
Chow A, Lucas D et al (2011) Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 208(2):261–271
De Haan G, Gerrits A (2007) Epigenetic control of hematopoietic stem cell aging the case of Ezh2. Ann N Y Acad Sci 1106:233–239
Dimitroff CJ, Lee JY et al (2001) CD44 is a major E-selectin ligand on human hematopoietic progenitor cells. J Cell Biol 153(6):1277–1286
Ding L, Morrison SJ (2013) Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495(7440):231–235
Ding L, Saunders TL et al (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481(7382):457–462
Donnini A, Re F et al (2007) Intrinsic and microenvironmental defects are involved in the age-related changes of Lin - c-kit+ hematopoietic progenitor cells. Rejuvenation Res 10(4):459–472
Dykstra B, de Haan G (2008) Hematopoietic stem cell aging and self-renewal. Cell Tissue Res 331(1):91–101
Fehrer C, Brunauer R et al (2007) Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan. Aging Cell 6(6):745–757
Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408(6809):239–247
Florian MC, Dorr K et al (2012) Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10(5):520–530
Frenette PS, Pinho S et al (2013) Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol 31:285–316
Geoffroy V, Kneissel M et al (2002) High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage. Mol Cell Biol 22(17):6222–6233
Gonzalez-Nieto D, Li L et al (2012) Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood 119(22):5144–5154
Green CB, Takahashi JS et al (2008) The meter of metabolism. Cell 134(5):728–742
Greenbaum A, Hsu YM et al (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495(7440):227–230
Hanoun M, Frenette PS (2013) This niche is a maze; an amazing niche. Cell Stem Cell 12(4):391–392
Ishikawa ET, Cancelas JA (2012) Lack of communication rusts and ages stem cells. Cell Cycle 11(17):3149–3150
Ito K, Hirao A et al (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12(4):446–451
Ju Z, Rudolph KL (2006) Telomeres and telomerase in stem cells during aging and disease. Genome Dyn 1:84–103
Ju Z, Jiang H et al (2007) Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13(6):742–747
Katayama Y, Battista M et al (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124(2):407–421
Kawai M, Sousa KM et al (2010) The many facets of PPARgamma: novel insights for the skeleton. Am J Physiol Endocrinol Metab 299(1):E3–E9
Kawai M, de Paula FJ et al (2012) New insights into osteoporosis: the bone-fat connection. J Intern Med 272(4):317–329
Kenyon J, Gerson SL (2007) The role of DNA damage repair in aging of adult stem cells. Nucleic Acids Res 35(22):7557–7565
Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8(4):290–301
Kim M, Moon HB et al (2003) Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 996:195–208
Lansdorp PM (2005) Role of telomerase in hematopoietic stem cells. Ann N Y Acad Sci 1044:220–227
Larsson J, Ohishi M et al (2008) Nf2/merlin regulates hematopoietic stem cell behavior by altering microenvironmental architecture. Cell Stem Cell 3(2):221–227
Lewinsohn DM, Nagler A et al (1990) Hematopoietic progenitor cell expression of the H-CAM (CD44) homing-associated adhesion molecule. Blood 75(3):589–595
Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327(5965):542–545
Li F, Jin F et al (2001) Impaired regeneration of the peripheral B cell repertoire from bone marrow following lymphopenia in old mice. Eur J Immunol 31(2):500–505
Li Z, Liu C et al (2011) Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. PLoS One 6(6), e20526
Liang Y, Van Zant G et al (2005) Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106(4):1479–1487
Lichtman MA (1981) The ultrastructure of the hemopoietic environment of the marrow: a review. Exp Hematol 9(4):391–410
Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5(2):133–139
Liu H, Fergusson MM et al (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317(5839):803–806
Massberg S, Schaerli P et al (2007) Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131(5):994–1008
Mendez-Ferrer S, Lucas D et al (2008) Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452(7186):442–447
Mendez-Ferrer S, Chow A et al (2009) Circadian rhythms influence hematopoietic stem cells. Curr Opin Hematol 16(4):235–242
Mendez-Ferrer S, Michurina TV et al (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466(7308):829–834
Meunier P, Aaron J et al (1971) Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin Orthop Relat Res 80:147–154
Moerman EJ, Teng K et al (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3(6):379–389
Nagasawa T, Hirota S et al (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382(6592):635–638
Nagasawa T, Omatsu Y et al (2011) Control of hematopoietic stem cells by the bone marrow stromal niche: the role of reticular cells. Trends Immunol 32(7):315–320
Naveiras O, Nardi V et al (2009) Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460(7252):259–263
Nilsson SK, Johnston HM et al (2001) Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97(8):2293–2299
Nombela-Arrieta C, Pivarnik G et al (2013) Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol 15(5):533–543
Ohneda O, Ohneda K et al (2001) ALCAM (CD166): its role in hematopoietic and endothelial development. Blood 98(7):2134–2142
Omatsu Y, Sugiyama T et al (2010) The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33(3):387–399
Papayannopoulou T, Priestley GV et al (2001) Synergistic mobilization of hemopoietic progenitor cells using concurrent beta1 and beta2 integrin blockade or beta2-deficient mice. Blood 97(5):1282–1288
Park D, Sykes DB et al (2012) The hematopoietic stem cell niche. Front Biosci 17:30–39
Parmar K, Mauch P et al (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A 104(13):5431–5436
Plowden J, Renshaw-Hoelscher M et al (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3(4):161–167
Presley CA, Lee AW et al (2005) Bone marrow connexin-43 expression is critical for hematopoietic regeneration after chemotherapy. Cell Commun Adhes 12(5–6):307–317
Priestley GV, Scott LM et al (2006) Lack of alpha4 integrin expression in stem cells restricts competitive function and self-renewal activity. Blood 107(7):2959–2967
Rando TA (2006) Stem cells, ageing and the quest for immortality. Nature 441(7097):1080–1086
Ratajczak J, Shin DM et al (2011) Higher number of stem cells in the bone marrow of circulating low Igf-1 level Laron dwarf mice–novel view on Igf-1, stem cells and aging. Leukemia 25(4):729–733
Renault VM, Rafalski VA et al (2009) FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5(5):527–539
Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7(12):885–896
Rossi DJ, Bryder D et al (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102(26):9194–9199
Sackstein R (2011) The biology of CD44 and HCELL in hematopoiesis: the ‘step 2-bypass pathway’ and other emerging perspectives. Curr Opin Hematol 18(4):239–248
Sackstein R, Merzaban JS et al (2008) Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 14(2):181–187
Schajnovitz A, Itkin T et al (2011) 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(5):391–398
Scheiermann C, Kunisaki Y et al (2012) Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity 37(2):290–301
Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4(1–2):7–25
Solana R, Pawelec G et al (2006) Aging and innate immunity. Immunity 24(5):491–494
Song Z, Wang J et al (2010) Alterations of the systemic environment are the primary cause of impaired B and T lymphopoiesis in telomere-dysfunctional mice. Blood 115(8):1481–1489
Stephan RP, Reilly CR et al (1998) Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood 91(1):75–88
Stolzing A, Jones E et al (2008) Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev 129(3):163–173
Sugimura R, He XC et al (2012) Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell 150(2):351–365
Sullivan C, Chen Y et al (2011) Functional ramifications for the loss of P-selectin expression on hematopoietic and leukemic stem cells. PLoS One 6(10), e26246
Taniguchi Ishikawa E, Gonzalez-Nieto D et al (2012) Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci U S A 109(23):9071–9076
Taniguchi Ishikawa E, Chang KH et al (2013) Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated beta1/beta2-integrin trafficking. Nat Commun 4:1660
Trougakos IP, Pawelec G et al (2006) Clusterin/Apolipoprotein J up-regulation after zinc exposure, replicative senescence or differentiation of human haematopoietic cells. Biogerontology 7(5–6):375–382
Tzeng YS, Li H et al (2011) Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood 117(2):429–439
Vas V, Senger K et al (2012a) Aging of the microenvironment influences clonality in hematopoiesis. PLoS One 7(8), e42080
Vas V, Wandhoff C et al (2012b) Contribution of an aged microenvironment to aging-associated myeloproliferative disease. PLoS One 7(2), e31523
Wagner W, Saffrich R et al (2005) Hematopoietic progenitor cells and cellular microenvironment: behavioral and molecular changes upon interaction. Stem Cells 23(8):1180–1191
Wagner W, Wein F et al (2007) Adhesion of hematopoietic progenitor cells to human mesenchymal stem cells as a model for cell-cell interaction. Exp Hematol 35(2):314–325
Wagner W, Wein F et al (2008) Adhesion of human hematopoietic progenitor cells to mesenchymal stromal cells involves CD44. Cells Tissues Organs 188(1–2):160–169
Wagner W, Bork S et al (2010) How to track cellular aging of mesenchymal stromal cells? Aging (Albany NY) 2(4):224–230
Warren LA, Rossi DJ (2009) Stem cells and aging in the hematopoietic system. Mech Ageing Dev 130(1–2):46–53
Williams DA, Majumdar MK (1994) Analysis of steel factor (stem cell factor) isoforms in the hematopoietic microenvironment. Stem Cells 12(Suppl 1):67–74, discussion 75–67
Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6(2):93–106
Wright DE, Wagers AJ et al (2001) Physiological migration of hematopoietic stem and progenitor cells. Science 294(5548):1933–1936
Xie Y, Yin T et al (2009) Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457(7225):97–101
Xing Z, Ryan MA et al (2006) Increased hematopoietic stem cell mobilization in aged mice. Blood 108(7):2190–2197
Yamazaki S, Iwama A et al (2009) TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 113(6):1250–1256
Yamazaki S, Ema H et al (2011) Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147(5):1146–1158
Zanjani ED, Flake AW et al (1999) Homing of human cells in the fetal sheep model: modulation by antibodies activating or inhibiting very late activation antigen-4-dependent function. Blood 94(7):2515–2522
Zhang J, Niu C et al (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425(6960):836–841
Zhao T, Li J et al (2010) MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab 299(1):E110–E116
Zhu X, Gui J et al (2007) Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution. Aging Cell 6(5):663–672
Zsebo KM, Williams DA et al (1990) Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63(1):213–224
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag Wien
About this chapter
Cite this chapter
Cancelas, J.A., Chang, KH. (2015). Aging of the Hematopoietic Stem Cell Niches. In: Geiger, H., Jasper, H., Florian, M. (eds) Stem Cell Aging: Mechanisms, Consequences, Rejuvenation. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1232-8_12
Download citation
DOI: https://doi.org/10.1007/978-3-7091-1232-8_12
Publisher Name: Springer, Vienna
Print ISBN: 978-3-7091-1231-1
Online ISBN: 978-3-7091-1232-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)