Gerontology

Regenerative and Technological Section

Free Access

lin– Sca-1+ Cells and Age-Dependent Changes of Their Proliferation Potential Are Reliant on Mesenchymal Stromal Cells and Are Leukemia Inhibitory Factor Dependent

Schraml E.a, b · Fehrer C.c · Brunauer R.c · Lepperdinger G.c · Chesnokova V.d · Schauenstein K.a, †

Author affiliations

aInstitute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, Graz, bInstitute of Applied Microbiology, University of Natural Resources and Applied Life Sciences Vienna, Vienna, and cInstitute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria; dCedars-Sinai Medical Center, Los Angeles, Calif., USA

Corresponding Author

Günter Lepperdinger

Institute for Biomedical Aging Research, Austrian Academy of Sciences

Rennweg 10, AT–6020 Innsbruck (Austria)

Tel. +43 512 5839 1934, Fax +43 512 5839 198

E-Mail guenter.lepperdinger@oeaw.ac.at

Related Articles for ""

Gerontology 2008;54:312–323

Abstract

Aging as a process is paralleled by a variety of hematological alterations. Characteristic features are a diminished homeostatic control of blood cell production and a decline in immune functions. It is generally accepted that stromal cells play a basal role in hematopoiesis by providing survival and differentiation signals, by secreting cytokines, or through direct contact with hematopoietic stem cells, thereby supporting the generation and replenishment of hematopoi- etic progenitor cells (HPC). Here we demonstrated that HPC-related colony formation is positively influenced by mesenchymal stromal cells (MSCs) when grown in co-culture, in particular regarding the number of primary granulocyte/macrophage colony-forming units as well as with respect to the average size of the formed colonies. These effects were more pronounced when the MSCs originated from young donors than from old ones. Because leukemia inhibitory factor (LIF) plays an important role during hematopoiesis, properties of lin– Sca-1+ cells and MSCs derived from LIF-deficient mice (LIF–/–) were determined both ex vivo and in vitro. LIF–/– animals contain a significantly reduced number of lin– Sca-1+ cells, nevertheless the replating capacity of LIF–/– HPCs was found to be generally unchanged when compared to those from LIF+/+ animals. However, when cocultured with MSCs, LIF–/– lin– Sca-1+ cells exhibited comparable characteristics to HPCs derived from old wild-type animals.

© 2008 S. Karger AG, Basel




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References

  1. Pedemonte E, Benvenuto F, Casazza S, Mancardi G, Oksenberg J, Uccelli A, Baranzini S: The molecular signature of therapeutic mesenchymal stem cells exposes the architecture of the hematopoietic stem cell niche synapse. BMC Genomics 2007;8:65.
  2. Dar A, Kollet O, Lapidot T: Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in nod/scid chimeric mice. Exp Hematol 2006;34:967–975.
  3. Li N, Feugier P, Serrurrier B, Latger-Cannard V, Lesesve J, Stoltz J, Eljaafari A: Human mesenchymal stem cells improve ex vivo expansion of adult human CD34+ peripheral blood progenitor cells and decrease their allostimulatory capacity. Exp Hematol 2007;35:507–515.
  4. Deans R, Moseley A: Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000;28:875–884.
  5. Devine S: Mesenchymal stem cells: will they have a role in the clinic? J Cell Biochem Suppl 2002;38:73–79.
  6. Fujimoto N, Fujita S, Tsuji T, Toguchida J, Ida K, Suginami H, Iwata H: Microencapsulated feeder cells as a source of soluble factors for expansion of CD34(+) hematopoietic stem cells. Biomaterials 2007;28:4795–4805.
  7. Kadereit S, Deeds L, Haynesworth S, Koc O, Kozik M, Szekely E, Daum-Woods K, Goetchius G, Fu P, Welniak L, Murphy W, Laughlin M: Expansion of LTC-ICs and maintenance of p21 and BCL-2 expression in cord blood CD34(+)/CD38(–) early progenitors cultured over human MSCs as a feeder layer. Stem Cells 2002;20:573–582.
  8. Koh S, Choi H, Park E, Kang H, Ahn H, Shin H: Co-culture of human CD34+ cells with mesenchymal stem cells increases the survival of CD34+ cells against the 5-aza-deoxycytidine- or trichostatin A-induced cell death. Biochem Biophys Res Commun 2005;329:1039–1045.
  9. Fehrer C, Lepperdinger G: Mesenchymal stem cell aging. Exp Gerontol 2005;40:926–930.
  10. Hatakeyama S, Yada M, Matsumoto M, Ishida N, Nakayama K: U box proteins as a new family of ubiquitin-protein ligases. J Biol Chem 2001;276:33111–33120.
  11. Löscher M, Fortschegger K, Ritter G, Wostry M, Voglauer R, Schmid J, Watters S, Rivett A, Ajuh P, Lamond A, Katinger H, Grillari J: Interaction of U-box e3 ligase SNEV with PSMB4, the beta7 subunit of the 20 S proteasome. Biochem J 2005;388:593–603.
  12. Mahajan K, Mitchell B: Role of human Pso4 in mammalian DNA repair and association with terminal deoxynucleotidyl transferase. Proc Natl Acad Sci USA 2003;100:10746–10751.
  13. Zhang N, Kaur R, Lu X, Shen X, Li L, Legerski R: The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. J Biol Chem 2005;280:40559–40567.
  14. Grillari J, Ajuh P, Stadler G, Löscher M, Voglauer R, Ernst W, Chusainow J, Eisenhaber F, Pokar M, Fortschegger K, Grey M, Lamond A, Katinger H: Snev is an evolutionarily conserved splicing factor whose oligomerization is necessary for spliceosome assembly. Nucleic Acids Res 2005;33:6868–6883.
  15. Fortschegger K, Wagner B, Voglauer R, Katinger H, Sibilia M, Grillari J: Early embryonic lethality of mice lacking the essential protein SNEV. Mol Cell Biol 2007;27:3123–3130.
  16. Grillari J, Hohenwarter O, Grabherr R, Katinger H: Subtractive hybridization of mRNA from early passage and senescent endothelial cells. Exp Gerontol 2000;35:187–197.
  17. Voglauer R, Chang M, Dampier B, Wieser M, Baumann K, Sterovsky T, Schreiber M, Katinger H, Grillari J: SNEV overexpression extends the life span of human endothelial cells. Exp Cell Res 2006;312:746–759.
  18. Brown M, Metcalf D, Gough N: Leukaemia inhibitory factor and interleukin 6 are expressed at very low levels in the normal adult mouse and are induced by inflammation. Cytokine 1994;6:300–309.
  19. Szilvassy S, Weller K, Lin W, Sharma A, Ho A, Tsukamoto A, Hoffman R, Leiby K, Gearing D: Leukemia inhibitory factor upregulates cytokine expression by a murine stromal cell line enabling the maintenance of highly enriched competitive repopulating stem cells. Blood 1996;87:4618–4628.
  20. Metcalf D: The unsolved enigmas of leukemia inhibitory factor. Stem Cells 2003;21:5–14.
  21. Falconi D, Oizumi K, Aubin J: Leukemia inhibitory factor influences the fate choice of mesenchymal progenitor cells. Stem Cells 2007;25:305–312.
  22. Oshima K, Teo D, Senn P, Starlinger V, Heller S: LIF promotes neurogenesis and maintains neural precursors in cell populations derived from spiral ganglion stem cells. BMC Dev Biol 2007;7:112.
  23. Li F, Liu Y, Chen D, Lin X, Li J, Wang J, Peng Y, Wang S, Wang Y: Leukemia inhibitory factor-expressing human embryonic lung fibroblasts as feeder cells for human embryonic germ cells. Cells Tissues Organs 2007;186:221–228.
  24. Strobel E, Möbest D, von Kleist S, Dangel M, Ries S, Mertelsmann R, Henschler R: Adhesion and migration are differentially regulated in hematopoietic progenitor cells by cytokines and extracellular matrix. Blood 1997;90:3524–3532.
  25. Morrison S, Qian D, Jerabek L, Thiel B, Park I, Ford P, Kiel M, Schork N, Weissman I, Clarke M: A genetic determinant that specifically regulates the frequency of hematopoietic stem cells. J Immunol 2002;168:635–642.
  26. Sudo K, Ema H, Morita Y, Nakauchi H: Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 2000;192:1273–1280.
  27. Stewart C, Kaspar P, Brunet L, Bhatt H, Gadi I, Köntgen F, Abbondanzo S: Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 1992;359:76–79.
  28. Chesnokova V, Auernhammer C, Melmed S: Murine leukemia inhibitory factor gene disruption attenuates the hypothalamo-pituitary-adrenal axis stress response. Endocrinology 1998;139:2209–2216.
  29. Gordon M, Marley S, Lewis J, Davidson R, Nguyen D, Grand F, Amos T, Goldman J: Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM. J Clin Invest 1998;102:710–715.
  30. Marley S, Lewis J, Zheng B, Davidson R, Davis J, McDonald C, Alenzi F, Goldman J, Gordon M: Peripheral blood progenitor cell mobilisation alters myeloid, but not erythroid, progenitor cell self-renewal kinetics. Bone Marrow Transplant 2001;27:241–248.
  31. Withey J, Marley S, Kaeda J, Harvey A, Crompton M, Gordon M: Targeting primary human leukaemia cells with RNA interference: Bcr-Abl targeting inhibits myeloid progenitor self-renewal in chronic myeloid leukaemia cells. Br J Haematol 2005;129:377–380.
  32. Schraml E, Voglauer R, Fortschegger K, Sibilia M, Stelzer I, Grillari J, Schauenstein K: Haploinsufficiency of SNEV causes defects of hematopoietic stem cells functions. Stem Cells Dev 2008;17:355–366.
  33. Balduino A, Hurtado S, Frazão P, Takiya C, Alves L, Nasciutti L, El-Cheikh M, Borojevic R: Bone marrow subendosteal microenvironment harbours functionally distinct haemosupportive stromal cell populations. Cell Tissue Res 2005;319:255–266.
  34. Deguchi K, Yagi H, Inada M, Yoshizaki K, Kishimoto T, Komori T: Excessive extramedullary hematopoiesis in Cbfa1-deficient mice with a congenital lack of bone marrow. Biochem Biophys Res Commun 1999;255:352–359.
  35. Calvi L, Adams G, Weibrecht K, Weber J, Olson D, Knight M, Martin R, Schipani E, Divieti P, Bringhurst F, Milner L, Kronenberg H, Scadden D: Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841–846.
  36. Visnjic D, Kalajzic Z, Rowe D, Katavic V, Lorenzo J, Aguila H: Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 2004;103:3258–3264.
  37. Dykstra B, de Haan G: Hematopoietic stem cell aging and self-renewal. Cell Tissue Res 2008;331:91–101.
  38. Osawa M, Hanada K, Hamada H, Nakauchi H: Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 1996;273:242–245.
  39. de Haan G, Van Zant G: Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene. J Exp Med 1997;186:529–536.
  40. de Haan G, Nijhof W, Van Zant G: Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood 1997;89:1543–1550.
  41. Kim D, Yoo K, Choi K, Choi J, Choi S, Yang S, Yang Y, Im H, Kim K, Jung H, Sung K, Koo H: Gene expression profile of cytokine and growth factor during differentiation of bone marrow-derived mesenchymal stem cell. Cytokine 2005;31:119–126.
  42. Bilko N, Votyakova I, Vasylovska S, Bilko D: Characterization of the interactions between stromal and haematopoietic progenitor cells in expansion cell culture models. Cell Biol Int 2005;29:83–86.
  43. Johnson F, Sinclair D, Guarente L: Molecular biology of aging. Cell 1999;96:291–302.
  44. Bellantuono I: Haemopoietic stem cells. Int J Biochem Cell Biol 2004;36:607–620.
  45. Spangrude G, Heimfeld S, Weissman I: Purification and characterization of mouse hematopoietic stem cells. Science 1988;241:58–62.
  46. Metcalf D, Nicola N, Gearing D: Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice. Blood 1990;76:50–56.
  47. Metcalf D, Hilton D, Nicola N: Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro. Blood 1991;77:2150–2153.
  48. Imamura M, Zhu X, Han M, Kobayashi M, Hashino S, Tanaka J, Kobayashi S, Kasai M, Asaka M: In vitro expansion of murine hematopoietic progenitor cells by leukemia inhibitory factor, stem cell factor, and interleukin-1 beta. Exp Hematol 1996;24:1280–1288.
  49. Shih C, Hu M, Hu J, Medeiros J, Forman S: Long-term ex vivo maintenance and expansion of transplantable human hematopoietic stem cells. Blood 1999;94:1623–1636.
  50. Shih C, Hu M, Hu J, Weng Y, Yazaki P, Medeiros J, Forman S: A secreted and LIF-mediated stromal cell-derived activity that promotes ex vivo expansion of human hematopoietic stem cells. Blood 2000;95:1957–1966.

Article / Publication Details

First-Page Preview
Abstract of Regenerative and Technological Section

Received: March 11, 2008
Accepted: July 28, 2008
Published online: October 08, 2008
Issue release date: October 2008

Number of Print Pages: 12
Number of Figures: 6
Number of Tables: 1

ISSN: 0304-324X (Print)
eISSN: 1423-0003 (Online)

For additional information: https://www.karger.com/GER


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