Skip to main content

Advertisement

SpringerLink
Log in

Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Neural stem cells are present in the human post-natal brain and are important in the development of brain tumours. However, their contribution to non-neoplastic human disease is less clear. We have tested the hypothesis that malformations of cortical development contain abnormal (pathological) stem cells. Such malformations are a major cause of epilepsy. Two of the most common malformations [focal cortical dysplasia (FCD) and cortical tubers] are characterised by the presence of a population of abnormal cells known as balloon cells. The identity of these cells is unknown but one hypothesis is that they are an abnormal stem cell that contributes to the pathogenesis of the malformation. We have characterised in tissue, and isolated in culture, an undifferentiated population of balloon cells from surgical resections of FCD and cortical tubers. We show that β1-integrin labels a sub-population of balloon cells with a stem cell phenotype and show for the first time that these cells can be isolated in vitro. We have characterised the immunohistochemical, morphological and ultrastructural features of these cells. This is the first isolation of an abnormal cell with features of a progenitor/stem cell from a non-neoplastic disease of the brain.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Baybis M, Yu J, Lee A et al (2004) mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol 56(4):478–487

    Article  CAS  PubMed  Google Scholar 

  2. D’Souza AD, Parikh N, Kaech SM, Shadel GS (2007) Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation. Mitochondrion 7(6):374–385

    Article  PubMed  Google Scholar 

  3. Farkas LM, Huttner WB (2008) The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development. Curr Opin Cell Biol 20(6):707–715

    Article  CAS  PubMed  Google Scholar 

  4. Harvey AS, Cross JH, Shinnar S, Mathern BW, Taskforce IPESS (2008) Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 49(1):146–155

    Article  PubMed  Google Scholar 

  5. Jacques TS, Relvas JB, Nishimura S et al (1998) Neural precursor cell chain migration and division are regulated through different beta1 integrins. Development 125(16):3167–3177

    CAS  PubMed  Google Scholar 

  6. Jacques TS, Skepper JN, Navaratnam V (1999) Fibroblast growth factor-1 improves the survival and regeneration of rat vagal preganglionic neurones following axon injury. Neurosci Lett 276(3):197–200

    Article  CAS  PubMed  Google Scholar 

  7. Jacques TS, Swales A, Brzozowski MJ et al (2010) Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. EMBO J 29(1):222–235

    Article  CAS  PubMed  Google Scholar 

  8. Ljungberg MC, Bhattacharjee MB, Lu Y et al (2006) Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60(4):420–429

    Article  CAS  PubMed  Google Scholar 

  9. Luo B-H, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647

    Article  CAS  PubMed  Google Scholar 

  10. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307–318

    Article  PubMed  Google Scholar 

  11. Milner R, Ffrench-Constant C (1994) A developmental analysis of oligodendroglial integrins in primary cells: changes in alpha v-associated beta subunits during differentiation. Development 120(12):3497–3506

    CAS  PubMed  Google Scholar 

  12. Miyata H, Chiang ACY, Vinters HV (2004) Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol 56(4):510–519

    Article  CAS  PubMed  Google Scholar 

  13. Morshead CM, van der Kooy D (2004) Disguising adult neural stem cells. Curr Opin Neurobiol 14(1):125–131

    Article  CAS  PubMed  Google Scholar 

  14. Okano H, Sawamoto K (2008) Neural stem cells: involvement in adult neurogenesis and CNS repair. Philos Trans R Soc Lond B Biol Sci 363(1500):2111–2122

    Article  PubMed  Google Scholar 

  15. Palmini A, Najm I, Avanzini G et al (2004) Terminology and classification of the cortical dysplasias. Neurology 62(6 Suppl 3):S2–S8

    Google Scholar 

  16. Persad S, Attwell S, Gray V et al (2001) Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 276(29):27462–27469

    Article  CAS  PubMed  Google Scholar 

  17. Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17(6):596–603

    Article  CAS  PubMed  Google Scholar 

  18. Schick V, Majores M, Engels G et al (2007) Differential Pi3 K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells. Brain Pathol 17(2):165–173

    Article  CAS  PubMed  Google Scholar 

  19. Schick V, Majores M, Koch A et al (2007) Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions. Epilepsia 48(Suppl 5):65–73

    Article  CAS  PubMed  Google Scholar 

  20. Stiles CD, Rowitch DH (2008) Glioma stem cells: a midterm exam. Neuron 58(6):832–846

    Article  CAS  PubMed  Google Scholar 

  21. Thom M, Martinian L, Sen A et al (2007) An investigation of the expression of G1-phase cell cycle proteins in focal cortical dysplasia type IIB. J Neuropathol Exp Neurol 66(11):1045–1055

    Article  CAS  PubMed  Google Scholar 

  22. Thom M, Martinian L, Sisodiya SM et al (2005) Mcm2 labelling of balloon cells in focal cortical dysplasia. Neuropathol Appl Neurobiol 31(6):580–588

    Article  CAS  PubMed  Google Scholar 

  23. Urbach H, Scheffler B, Heinrichsmeier T et al (2002) Focal cortical dysplasia of Taylor’s balloon cell type: a clinicopathological entity with characteristic neuroimaging and histopathological features, and favorable postsurgical outcome. Epilepsia 43(1):33–40

    Article  PubMed  Google Scholar 

  24. Vinters HV, Miyata H (2004) Tuberous Sclerosis. In: Golden JA, Harding BN (eds) Developmental Neuropathology. International Society of Neuropathology, Basel, pp 79–87

    Google Scholar 

  25. Wong M (2009) Animal models of focal cortical dysplasia and tuberous sclerosis complex: recent progress toward clinical applications. Epilepsia 50(Suppl 9):34–44

    Article  CAS  PubMed  Google Scholar 

  26. Ying Z, Gonzalez-Martinez J, Tilelli C, Bingaman W, Najm I (2005) Expression of neural stem cell surface marker CD133 in balloon cells of human focal cortical dysplasia. Epilepsia 46(11):1716–1723

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The Great Ormond Street Hospital Children’s Charity and the Pathological Society of Great Britain have funded this research. We are grateful to Nigel Weaving, Lillian Martinen and Kerrie Venner for technical assistance and to Janette Gardener for administrative assistance.

Conflict of interest statement

None.

Author information

Authors and Affiliations

  1. Department of Histopathology, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK

    Shireena A. Yasin, Kate Latak, Francesca Becherini, Anita Ganapathi, Khadijah Miller, Oliver Campos, Simon R. Picker, Nelly Bier, Glenn Anderson, Brian Harding & Thomas S. Jacques

  2. Department of Neurology, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK

    Martin Smith & J. Helen Cross

  3. Department of Neurosurgery, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK

    William Harkness

  4. Neural Development Unit, UCL-Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    Shireena A. Yasin, Kate Latak, Anita Ganapathi, Khadijah Miller, Oliver Campos, Simon R. Picker & Thomas S. Jacques

  5. The Neuroscience Unit, UCL-Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    J. Helen Cross & Brian Harding

  6. UCL-Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Maria Thom

Authors
  1. Shireena A. Yasin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kate Latak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca Becherini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anita Ganapathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Khadijah Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Oliver Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Simon R. Picker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nelly Bier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Martin Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maria Thom
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Glenn Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J. Helen Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. William Harkness
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Brian Harding
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Thomas S. Jacques
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas S. Jacques.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2010_677_MOESM1_ESM.rtf

Supplementary material 1. Clinical characteristics of FCDIIb and TSC cases from which were used for culture experiments. (RTF 45 kb)

401_2010_677_MOESM2_ESM.tif

Supplementary material 2. β1-integrin-positive (green) balloon cells in vivo shown by confocal microscopy. Scale bar 25μm. (TIFF 5491 kb)

401_2010_677_MOESM3_ESM.tif

Supplementary material 3. β1-integrin positive balloon cells in vivo lack markers of mature neurones or glia. The bar chart shows the percentage of β1-positive or negative cells that are positive for each lineage marker. No β1-positive cells expressed Neurofilament. Very rare β1-positive cells expressed GFAP (3.1%). The difference between the β1-positive and negative cells reached statistical significance (p<0.05 Χ2 interactions between β1 expression and all differentiation markers 3 independent cases of FCD and >3000 cells). (TIFF 172 kb)

401_2010_677_MOESM4_ESM.doc

Supplementary material 4. Cultured balloon cells were isolated from 10 out of 12 cases of FCD TypeIIb or cortical tubers but no cases of other epilepsy associated pathology. (DOC 197 kb)

401_2010_677_MOESM5_ESM.mov

Supplementary material 5. Balloon cells are dynamic in culture, going through repeated rounds of cell attachment and cell separation with other balloon cells in culture. The images are from a case of cortical tuber (time-lapse microscopy 10 mins/frame). The material between the cells is myelin debris (confirmed by electron microscopy). The balloon cells are the only reproducible cell population in the cultures. (MOV 10250 kb)

401_2010_677_MOESM6_ESM.doc

Supplementary material 6. The presence of large cells in culture correlates closely with the presence of histologically confirmed balloon cells in the adjacent tissue (p<0.001 Fisher’s exact test). The case with no balloon cells in the immediately adjacent tissue did have proven balloon cells elsewhere in the tissue. (DOC 196 kb)

Supplementary material 7. Quantification of in vitro cell immunophenotyping. (DOCX 52 kb)

401_2010_677_MOESM8_ESM.tif

Supplementary material 8. Cultured balloon cells retain expression of markers of stem cells or progenitor cells after one week in culture. Each row represents a single balloon cell stained by immunofluorescence with a single marker. 1-3 and 5 confocal images. Scale bar 25μm. (TIFF 3473 kb)

Supplementary material 9. The video shows a balloon cell stained with mitotracker (red), vimentin (green) and DAPI (blue). The cell has the typical binucleate morphology. The vimentin appears to stain predominantly the cortex of the cell with mitochondria being more concentrated within the centre. The image is a projected z-stack from confocal images. (MOV 3504 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yasin, S.A., Latak, K., Becherini, F. et al. Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol 120, 85–96 (2010). https://doi.org/10.1007/s00401-010-0677-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0677-y

Keywords

Search

Navigation