Skip to main content
SpringerLink
Log in

Regeneration After Injury: Activation of Stem Cell Stress Response Pathways to Rapidly Repair Tissues

  • Chapter
  • First Online:
Adult Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Stem cells play key roles in the development of tissues and maintain tissue homeostasis. Because of these properties a great deal of research is focused on exploiting tissue stem cells as a means to treat degenerative diseases. In fact recent advances in the derivation of tissue stem cell populations from embryonic stem (ES) cells or induced pluripotent stem (iPS) cells hold great promise for the development of new therapies. Unfortunately much of this promise has not been fulfilled. An alternative approach is to examine the mechanisms by which tissues respond to injury and regenerate. In this chapter, we will discuss a number of different strategies that stem cells use to repair injured tissue that differ from the mechanisms that regulate homeostatic maintenance of the tissue. Although this discussion only touches on a few examples, each situation has direct implications for therapy development, which would suggest that tissue regeneration may be more complicated than transplanting ES- or iPS-derived stem cells into patients.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

b-gal:

Beta-galactosidase

BMP4:

Bone morphogenetic protein 4

BrdU:

Bromo-deoxyuridine

Epo:

Erythropoietin

ES:

Embryonic stem

GM-CSF:

Granulocyte macrophage colony-stimulating factor

H2B-CreA:

Histone 2B CreA fusion protein

H2B-YFP:

Histone 2B YFP fusion protein

HH:

Hedgehog

HSC:

Hematopoietic stem cell

Ifng:

Interferon gamma

IL-7Ra:

Interleukin 7 receptor alpha

iPS:

Induced pluripotent stem

KSL:

Kit+Sca1+Lineage−

LPS:

Lipopolysaccharide

LRC:

Label-retaining cell

M-CSF:

Macrophage colony-stimulating factor

SCF:

Stem cell factor

TLR:

Toll-like receptor

TNFa:

Tumor necrosis factor alpha

YFP:

Yellow fluorescent protein

References

  1. Bryder D, Rossi DJ, Weissman IL (2006) Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol 169(2):338–346

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Weissman I (2012) Stem cell therapies could change medicine… if they get the chance. Cell Stem Cell 10(6):663–665

    Article  PubMed  CAS  Google Scholar 

  3. Okano H et al (2013) Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res 112(3):523–533

    Article  PubMed  CAS  Google Scholar 

  4. Yamanaka S (2012) Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10(6):678–684

    Article  PubMed  CAS  Google Scholar 

  5. Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1(1):39–49

    Article  PubMed  CAS  Google Scholar 

  6. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  PubMed  CAS  Google Scholar 

  7. Hanna J et al (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318(5858):1920–1923

    Article  PubMed  CAS  Google Scholar 

  8. Cheshier SH et al (1999) In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci U S A 96(6):3120–3125

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Copley MR, Beer PA, Eaves CJ (2012) Hematopoietic stem cell heterogeneity takes center stage. Cell Stem Cell 10(6):690–697

    Article  PubMed  CAS  Google Scholar 

  10. Barker N, van de Wetering M, Clevers H (2008) The intestinal stem cell. Genes Dev 22(14):1856–1864

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Barker N et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007

    Article  PubMed  CAS  Google Scholar 

  12. Barker N, van Oudenaarden A, Clevers H (2012) Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell 11(4):452–460

    Article  PubMed  CAS  Google Scholar 

  13. Buczacki SJ et al (2013) Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495(7439):65–69

    Article  PubMed  CAS  Google Scholar 

  14. Munoz J et al (2012) The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J 31(14):3079–3091

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Takeda N et al (2011) Interconversion between intestinal stem cell populations in distinct niches. Science 334(6061):1420–1424

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Sangiorgi E, Capecchi MR (2008) Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40(7):915–920

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Bevins CL, Salzman NH (2011) Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol 9(5):356–368

    Article  PubMed  CAS  Google Scholar 

  18. Lopez-Garcia C et al (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330(6005):822–825

    Article  PubMed  CAS  Google Scholar 

  19. Sato T et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265

    Article  PubMed  CAS  Google Scholar 

  20. Jullien N et al (2007) Conditional transgenesis using Dimerizable Cre (DiCre). PLoS One 2(12):e1355

    Article  PubMed Central  PubMed  Google Scholar 

  21. Jullien N et al (2003) Regulation of Cre recombinase by ligand-induced complementation of inactive fragments. Nucleic Acids Res 31(21):e131

    Article  PubMed Central  PubMed  Google Scholar 

  22. Weissman IL, Shizuru JA (2008) The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood 112(9):3543–3553

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Doulatov S et al (2012) Hematopoiesis: a human perspective. Cell Stem Cell 10(2):120–136

    Article  PubMed  CAS  Google Scholar 

  24. Ergen AV et al (2013) Isolation and characterization of mouse side population cells. Methods Mol Biol 946:151–162

    Article  PubMed  CAS  Google Scholar 

  25. Mayle A et al (2013) Flow cytometry analysis of murine hematopoietic stem cells. Cytometry A 83(1):27–37

    Article  PubMed Central  PubMed  Google Scholar 

  26. Osawa M et al (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273(5272):242–245

    Article  PubMed  CAS  Google Scholar 

  27. Dykstra B et al (2007) Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell 1(2):218–229

    Article  PubMed  CAS  Google Scholar 

  28. Benz C et al (2012) Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell 10(3):273–283

    Article  PubMed  CAS  Google Scholar 

  29. Traver D et al (2001) Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets. Blood 98(3):627–635

    Article  PubMed  CAS  Google Scholar 

  30. Akashi K et al (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404(6774):193–197

    Article  PubMed  CAS  Google Scholar 

  31. Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91(5):661–672

    Article  PubMed  CAS  Google Scholar 

  32. Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30(1):16–34

    Article  PubMed  CAS  Google Scholar 

  33. Kumar H, Kawai T, Akira S (2009) Toll-like receptors and innate immunity. Biochem Biophys Res Commun 388(4):621–625

    Article  PubMed  CAS  Google Scholar 

  34. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    Article  PubMed  CAS  Google Scholar 

  35. Medzhitov R, Janeway CA Jr (1999) Innate immune induction of the adaptive immune response. Cold Spring Harb Symp Quant Biol 64:429–435

    Article  PubMed  CAS  Google Scholar 

  36. King KY, Goodell MA (2011) Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat Rev Immunol 11(10):685–692

    Article  PubMed  CAS  Google Scholar 

  37. Baldridge MT, King KY, Goodell MA (2011) Inflammatory signals regulate hematopoietic stem cells. Trends Immunol 32(2):57–65

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Belyaev NN et al (2010) Induction of an IL7-R(+)c-Kit(hi) myelolymphoid progenitor critically dependent on IFN-gamma signaling during acute malaria. Nat Immunol 11(6):477–485

    Article  PubMed  CAS  Google Scholar 

  39. Young HA, Hardy KJ (1995) Role of interferon-gamma in immune cell regulation. J Leukoc Biol 58(4):373–381

    PubMed  CAS  Google Scholar 

  40. Su Z, Stevenson MM (2000) Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection. Infect Immun 68(8):4399–4406

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. Libregts SF et al (2011) Chronic IFN-gamma production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood 118(9):2578–2588

    Article  PubMed  CAS  Google Scholar 

  42. Felli N et al (2005) Multiple members of the TNF superfamily contribute to IFN-gamma-mediated inhibition of erythropoiesis. J Immunol 175(3):1464–1472

    Article  PubMed  CAS  Google Scholar 

  43. Boiko JR, Borghesi L (2012) Hematopoiesis sculpted by pathogens: Toll-like receptors and inflammatory mediators directly activate stem cells. Cytokine 57(1):1–8

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Nagai Y et al (2006) Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24(6):801–812

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Kouskoff V et al (1996) Organ-specific disease provoked by systemic autoimmunity. Cell 87(5):811–822

    Article  PubMed  CAS  Google Scholar 

  46. Ma YD et al (2009) Defects in osteoblast function but no changes in long-term repopulating potential of hematopoietic stem cells in a mouse chronic inflammatory arthritis model. Blood 114(20):4402–4410

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Oduro KA Jr et al (2012) Myeloid skewing in murine autoimmune arthritis occurs in hematopoietic stem and primitive progenitor cells. Blood 120(11):2203–2213

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Ehrchen JM et al (2009) The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86(3):557–566

    Article  PubMed  CAS  Google Scholar 

  49. Vogl T et al (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13(9):1042–1049

    Article  PubMed  CAS  Google Scholar 

  50. Youssef P et al (1999) Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol 26(12):2523–2528

    PubMed  CAS  Google Scholar 

  51. Paulson RF, Shi L, Wu DC (2011) Stress erythropoiesis: new signals and new stress progenitor cells. Curr Opin Hematol 18(3):139–145

    Article  PubMed Central  PubMed  Google Scholar 

  52. Hara H, Ogawa M (1976) Erythropoietic precursors in mice with phenylhydrazine-induced anemia. Am J Hematol 1:4530458

    Article  Google Scholar 

  53. Hara H, Ogawa M (1977) Erythropoietic precursors in mice under erythropoietic stimulation and suppression. Exp Hematol 5(2):141–148

    PubMed  CAS  Google Scholar 

  54. Bunn HF (2013) Erythropoietin. Cold Spring Harb Perspect Med 3(3):a011619

    Article  PubMed  Google Scholar 

  55. Ebert BL, Bunn HF (1999) Regulation of the erythropoietin gene. Blood 94(6):1864–1877

    PubMed  CAS  Google Scholar 

  56. Cole R, Regan T (1976) Haematopoietic progenitor cells in the prenatal conegenitally anaemic “Flexed-tail” (f/f) mice. Br J Haematol 33:387–394

    Article  PubMed  CAS  Google Scholar 

  57. Gruneberg H (1942) The anaemia of the flexed-tail mice (Mus musculus L.) II. Siderocytes. J Genet 44:246–271

    Article  Google Scholar 

  58. Gruneberg H (1942) The anaemia of the flexed-tail mouse (Mus musculus L.) I. Static and dynamic haematology. J Genet 43:45–68

    Article  Google Scholar 

  59. Lenox L, Perry J, Paulson R (2005) BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood 105:2741–2748

    Article  PubMed  CAS  Google Scholar 

  60. Mixter R, Hunt H (1933) Anemia in the flexed tailed mouse, Mus musculus. Genetics 18:367–387

    PubMed Central  PubMed  CAS  Google Scholar 

  61. Perry J, Harandi O, Paulson R (2007) BMP4, SCF and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Blood 109:4494–4502

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Wu DC, Paulson RF (2010) Hypoxia regulates BMP4 expression in the murine spleen during the recovery from acute anemia. PLoS One 5(6):e11303

    Article  PubMed Central  PubMed  Google Scholar 

  63. Perry JM et al (2009) Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling. Blood 113(4):911–918

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Harandi OF et al (2010) Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors. J Clin Invest 120(12):4507–4519

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Zhang J et al (2003) Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood 102(12):3938–3946

    Article  PubMed  CAS  Google Scholar 

  66. Paquette R, Dorshkind K (2002) Optimizing hematopoietic recovery following bone marrow transplantation. J Clin Invest 109(12):1527–1528

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Na Nakorn T et al (2002) Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S. J Clin Invest 109(12):1579–1585

    Article  PubMed Central  PubMed  Google Scholar 

  68. BitMansour A et al (2005) Single infusion of myeloid progenitors reduces death from Aspergillus fumigatus following chemotherapy-induced neutropenia. Blood 105(9):3535–3537

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Slayton WB et al (2002) The spleen is a major site of megakaryopoiesis following transplantation of murine hematopoietic stem cells. Blood 100(12):3975–3982

    Article  PubMed  CAS  Google Scholar 

  70. Hofmann I et al (2009) Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 4(6):559–567

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  71. Gao J et al (2009) Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 4(6):548–558

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Intercollege Graduate Program in Genetics, and Cell and Developmental Biology Graduate Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA

    Robert F. Paulson Ph.D.

  2. Intercollege Graduate Program in Genetics, The Pennsylvania State University, University Park, PA, 16802, USA

    Laura Bennett

  3. Cell and Developmental Biology Graduate Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA

    Jie Xiang

Authors
  1. Robert F. Paulson Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert F. Paulson Ph.D. .

Editor information

Editors and Affiliations

  1. Regenerative Medicine Program, Ottawa Hospital Research Institute Sprott Centre for Stem Cell Research, Ottawa, Ontario, Canada

    Kursad Turksen

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Paulson, R.F., Bennett, L., Xiang, J. (2014). Regeneration After Injury: Activation of Stem Cell Stress Response Pathways to Rapidly Repair Tissues. In: Turksen, K. (eds) Adult Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-9569-7_16

Download citation

Publish with us

Policies and ethics

Search

Navigation