Skip to main content

Mortalin and Stem Cells: A Study from Planarians

  • Chapter
  • First Online:
Mortalin Biology: Life, Stress and Death
  • 633 Accesses

Abstract

Adult stem cells are fundamental for physiological tissue renewal and regeneration after injury. The failure of stem cells to substitute dead or damaged cells is seen as one mechanism that limits the longevity of organisms. Planarian flatworms provide a unique model system to investigate in vivo the molecular machinery that controls adult stem cell functions in tissue renewal and repair. The extraordinary ability of planarians to regenerate whole animals from very small body fragments is in fact strictly associated with the unlimited growth potential of pluripotent stem cells, referred to as neoblasts. Neoblasts are distributed throughout the body and constantly undergo division to support continuous turnover of all specialized cell types. Moreover, upon amputation, these cells activate extensive proliferation to form the regenerative blastema, from which missing parts are regenerated. Damage or reduction in number of neoblasts deeply affects regeneration and planarian survival. Even though some progress has been made in identifying the genes that regulate self-renewal capacity and commitment of these cells, little is known about how these cells support continuous proliferative activity and long-term stability, maintaining control of cell division. I discuss evidence suggesting that Djmot, a planarian mortalin-like gene, significantly contributes to the mechanisms that regulate unlimited growth potential of stem cells in vivo, and I advance the hypothesis that its product plays a major role in keeping the activity of p53 under control in these cells.

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

Access this chapter

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

References

  • Adell T, Cebrià F, Saló E (2010) Gradients in planarian regeneration and homeostasis. Cold Spring Harb Perspect Biol 2(1):a000505

    Article  PubMed  Google Scholar 

  • Baguñà J (1976) Mitosis in the intact and regenerating planarian Dugesia mediterranea n. sp. I. Mitotic studies during growth, feeding and starvation. J Exp Zool 195:53–64

    Article  Google Scholar 

  • Baguñà J, Romero R (1981) Quantitative analysis of cell types during growth, degrowth and regeneration in the planarians Dugesia mediterranea and Dugesia tigrina. Hydrobiologia 84:181–194

    Article  Google Scholar 

  • Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E (2010) Lack of p21 links cell cycle control and appendage regeneration in mice. Proc Natl Acad Sci U S A 107:5845–5850

    Article  PubMed  CAS  Google Scholar 

  • Carette J, Lehnert S, Chow TY (2002) Implication of PBP74/mortalin/GRP75 in the radio-adaptive response. Int J Radiat Biol 78:183–190

    Article  PubMed  CAS  Google Scholar 

  • Conte M, Deri P, Isolani ME, Mannini L, Batistoni R (2009) A mortalin-like gene is crucial for planarian stem cell viability. Dev Biol 334:109–118

    Article  PubMed  CAS  Google Scholar 

  • Conte M, Deri P, Isolani ME, Mannini L, Batistoni R (2010) Characterization of hsp genes in planarian stem cells. Belg J Zool 140:137–143

    Google Scholar 

  • Conte M, Isolani ME, Deri P, Mannini L, Batistoni R (2011) Expression of hsp90 mediates cytoprotective effects in the gastrodermis of planarians. Cell Stress Chaperones 16:33–39

    Article  PubMed  CAS  Google Scholar 

  • De Mena L, Coto E, Sánchez-Ferrero E, Ribacoba R, Guisasola LM, Salvador C, Blázquez M, Alvarez V (2009) Mutational screening of the mortalin gene (HSPA9) in Parkinson’s disease. J Neural Transm 116:1289–1293

    Article  PubMed  Google Scholar 

  • Deocaris CC, Widodo N, Ishii T, Kaul SC, Wadhwa R (2007) Functional significance of minor structural and expression changes in stress chaperone mortalin. Ann NY Acad Sci 1119:165–175

    Article  PubMed  CAS  Google Scholar 

  • Deocaris CC, Kaul SC, Wadhwa R (2008) From proliferative to neurological role of an hsp70 stress chaperone, mortalin. Biogerontology 9:391–403

    Article  PubMed  CAS  Google Scholar 

  • Deocaris CC, Kaul SC, Wadhwa R (2009) The versatile stress protein mortalin as a chaperone therapeutic agent. Protein Pept Lett 16:517–529

    Article  PubMed  CAS  Google Scholar 

  • Eisenhoffer GT, Kang H, Sánchez Alvarado A (2008) Molecular analysis of stem cells and their descendants during cell turnover and regeneration in the planarian Schmidtea mediterranea. Cell Stem Cell 3:327–339

    Article  PubMed  CAS  Google Scholar 

  • Gabai VL, Yaglom JA, Waldman T, Sherman MY (2009) Heat shock protein hsp72 controls oncogene-induced senescence pathways in cancer cells. Mol Cell Biol 29:559–569

    Article  PubMed  CAS  Google Scholar 

  • Gentile L, Cebrià F, Bartscherer K (2011) The planarian flatworm: an in vivo model for stem cell biology and nervous system regeneration. Dis Model Mech 4:12–19

    Article  PubMed  CAS  Google Scholar 

  • González-Estévez C, Saló E (2010) Autophagy and apoptosis in planarians. Apoptosis 15:279–292

    Article  PubMed  Google Scholar 

  • Goss RJ (1969) Principles of Regeneration. Academic, New York

    Google Scholar 

  • Handberg-Thorsager M, Fernandez E, Saló E (2008) Stem cells and regeneration in planarians. Front Biosci 13:6374–6394

    Article  PubMed  CAS  Google Scholar 

  • Hayashi T, Asami M, Higuchi S, Shibata N, Agata K (2006) Isolation of planarian X-ray-sensitive stem cells by fluorescente-activated cell sorting. Dev Growth Differ 48:371–380

    Article  PubMed  Google Scholar 

  • Hayashi T, Shibata N, Okumura R, Kudome T, Nishimura O, Tarui H, Agata K (2010) Single-cell profiling of planarian stem cells using fluorescent activated cell sorting and its “index sorting” function for stem cell research. Dev Growth Differ 52:131–144

    Article  PubMed  CAS  Google Scholar 

  • Higuchi S, Hayashi T, Hori I, Shibata N, Sakamoto H, Agata K (2007) Characterization and categorization of fluorescence activated cell sorted planarian stem cells by ultrastructural analysis. Dev Growth Differ 49:571–581

    Article  PubMed  Google Scholar 

  • Kaul SC, Duncan EL, Englezou A, Takano S, Reddel RR, Mitsui Y, Wadhwa R (1998) Malignant transformation of NIH3T3 cells by overexpression of mot-2 protein. Oncogene 17:907–911

    Article  PubMed  CAS  Google Scholar 

  • Kaul SC, Reddel RR, Mitsui Y, Wadhwa R (2001) An N-terminal region of mot-2 binds to p53 in vitro. Neoplasia 3:110–114

    Article  PubMed  CAS  Google Scholar 

  • Kaul SC, Taira K, Pereira-Smith OM, Wadhwa R (2002) Mortalin: present and prospective. Exp Gerontol 37:1157–1164

    Article  PubMed  CAS  Google Scholar 

  • Kaul SC, Aida S, Yaguchi T, Kaur K, Wadhwa R (2005) Activation of wild type p53 function by its mortalin-binding, cytoplasmically localizing carboxyl terminus peptides. J Biol Chem 280:39373–39379

    Article  PubMed  CAS  Google Scholar 

  • Kaul Z, Yaguchi T, Kaul SC, Wadhwa R (2006) Quantum dot-based protein imaging and functional significance of two mitochondrial chaperones in cellular senescente and carcinogenesis. Ann N Y Acad Sci 1067:469–473

    Article  PubMed  CAS  Google Scholar 

  • Kaul SC, Deocaris CC, Wadhwa R (2007) Three faces of mortalin: a housekeeper, guardian and killer. Exp Gerontol 4:263–274

    Article  Google Scholar 

  • Kimura K, Tanaka N, Nakamura N, Takano S, Ohkuma S (2007) Knockdown of mitochondrial heat shock protein 70 promotes progeria-like phenotypes in Caenorhabditis elegans. J Biol Chem 282:5910–5918

    Article  PubMed  CAS  Google Scholar 

  • Iosefson O, Azem A (2010) Reconstitution of the mitochondrial Hsp70 (mortalin)-p53 interaction using purified proteins-identification of additional interacting regions. FEBS Lett 584:1080–1084

    Article  PubMed  CAS  Google Scholar 

  • Morgan TH (1901) Regeneration. Macmillan, New York

    Google Scholar 

  • Muller TL, Ngo-Muller V, Reginelli A, Taylor G, Anderson R, Muneoka K (1999) Regeneration in higher vertebrates: limb buds and digit tips. Semin Cell Dev Biol 10:405–413

    Article  PubMed  CAS  Google Scholar 

  • Muneoka K, Sassoon D (1992) Molecular aspects of regeneration in developing vertebrate limbs. Dev Biol 152:37–49

    Article  PubMed  CAS  Google Scholar 

  • O’Callaghan-Sunol C, Gabai VL, Sherman MY (2007) Hsp27 modulates p53 signaling and suppresses cellular senescence. Cancer Res 67:11779–11788

    Article  PubMed  Google Scholar 

  • Orii H, Sakurai T, Watanabe K (2005) Distribution of the stem cells (neoblasts) in the planarian Dugesia japonica. Dev Genes Evol 215:143–157

    Article  PubMed  CAS  Google Scholar 

  • Oviedo NJ, Nicolas CL, Adams DS, Levin M (2008) Planarians: a versatile and powerful model system for molecular studies of regeneration, adult stem cell regulation, aging, and behavior. Cold Spring Harb Protoc 11:10.1101/pdb.emo101

    Google Scholar 

  • Pearson BJ, Sánchez Alvarado A (2009) Regeneration, stem cells, and the evolution of tumor suppression. Cold Spring Harb Symp Quant Biol 73:565–572

    Article  Google Scholar 

  • Pearson BJ, Sánchez Alvarado A (2010) A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages. Development 137:213–221

    Article  PubMed  CAS  Google Scholar 

  • Pellettieri J, Sánchez Alvarado A (2007) Cell turnover and adult tissue homeostasis: from humans to planarians. Ann Rev Genet 41:83–105

    Article  PubMed  CAS  Google Scholar 

  • Prinsloo E, Setati MM, Longshaw VM, Blatch GL (2009) Chaperoning stem cells: a role for heat shock proteins in the modulation of stem cell self-renewal and differentiation? Bioessays 31:370–377

    Article  PubMed  CAS  Google Scholar 

  • Ran Q, Wadhwa R, Kawai R, Kaul SC, Sifers RN, Bick RJ, Smith JR, Pereira-Smith OM (2000) Extramitochondrial localization of mortalin/mthsp70/PBP74/GRP75. Biochem Biophys Res Commun 275:174–179

    Article  PubMed  CAS  Google Scholar 

  • Rossi L, Salvetti A, Marincola FM, Lena A, Deri P, Mannini L, Batistoni R, Wang E, Gremigni V (2007) Deciphering the molecular machinery of stem cells: a look at the neoblast gene expression profile. Genome Biol 8:R62

    Article  PubMed  Google Scholar 

  • Rossi L, Salvetti A, Batistoni R, Deri P, Gremigni V (2008) Planarians, a tale of stem cells. Cell Mol Life Sci 65:16–23

    Article  PubMed  CAS  Google Scholar 

  • Salvetti A, Rossi L, Deri P, Batistoni R (2000) An MCM2-related gene is expressed in proliferating cells of intact and regenerating planarians. Dev Dyn 218:603–614

    Article  PubMed  CAS  Google Scholar 

  • Sánchez-Alvarado A, Newmark PA (1999) Double-stranded RNA specifically disrupts gene expression during planarian regeneration. Proc Natl Acad Sci U S A 96:5049–5054

    Article  PubMed  Google Scholar 

  • Sharpless NE, Schatten G (2009) Stem cell aging. J Gerontol A Biol Sci Med Sci 64:202–204

    Article  PubMed  Google Scholar 

  • Sherman MY, Gabai V, O’Callaghan C, Yaglom J (2007) Molecular chaperones regulate p53 and suppress senescence programs. FEBS Lett 581:3711–3715

    Article  PubMed  CAS  Google Scholar 

  • Shibata N, Rouhana L, Agata K (2010) Cellular and molecular dissection of pluripotent adult somatic stem cells in planarians. Develop Growth Differ 52:27–41

    Article  CAS  Google Scholar 

  • Spradling A, Ganetsky B, Hieter P, Johnston M, Olson M, Orr-Weaver T, Rossant J, Sánchez Alvarado A, Waterston R (2006) New roles for model genetic organisms in understanding and treating human disease: Report from the 2006 Genetics Society of America Meeting Genetics 172:2025–2032

    Google Scholar 

  • Wadhwa R, Kaul SC, Mitsui Y, Sugimoto Y (1993) Differential subcellular distribution of mortalin in mortal and immortal mouse and human fibroblasts. Exp Cell Res 207:442–448

    Article  PubMed  CAS  Google Scholar 

  • Wadhwa R, Taira K, Kaul SC (2002) An HSP70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where? Cell Stress Chaperones 7:309–316

    Article  PubMed  CAS  Google Scholar 

  • Wadhwa R, Takano S, Kaur K, Deocaris CC, Pereira-Smith OM, Reddel RR, Kaul SC (2006) Upregulation of mortalin/mthsp70/Grp75 contributes to human carcinogenesis. Int J Cancer 118:2973–2980

    Article  PubMed  CAS  Google Scholar 

  • Walker C, Böttger S, Low B (2006) Mortalin-based cytoplasmic sequestration of p53 in a nonmammalian cancer model. Am J Pathol 168:1526–1530

    Article  PubMed  CAS  Google Scholar 

  • Yokoyama K, Fukumoto K, Murakami T (2002) Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot-2 (mortalin/mthhsp70/Grp75). FEBS Lett 516:53–57

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I greatly appreciate and thank colleagues and students who contributed to the main results mentioned in this review and also gratefully acknowledge the input provided through discussions and constructive criticisms.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Renata Batistoni .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Batistoni, R. (2012). Mortalin and Stem Cells: A Study from Planarians. In: Kaul, S., Wadhwa, R. (eds) Mortalin Biology: Life, Stress and Death. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-3027-4_7

Download citation

Publish with us

Policies and ethics