Advertisement

Neurochemical Research

, Volume 41, Issue 7, pp 1527–1544 | Cite as

A2B5+/GFAP+ Cells of Rat Spinal Cord Share a Similar Lipid Profile with Progenitor Cells: A Comparative Lipidomic Study

  • Yutaka Itokazu
  • Nobuyoshi Tajima
  • Laura Kerosuo
  • Pentti Somerharju
  • Hannu Sariola
  • Robert K. Yu
  • Reijo KäkeläEmail author
Original Paper

Abstract

The central nervous system (CNS) harbors multiple glial fibrillary acidic protein (GFAP) expressing cell types. In addition to the most abundant cell type of the CNS, the astrocytes, various stem cells and progenitor cells also contain GFAP+ populations. Here, in order to distinguish between two types of GFAP expressing cells with or without the expression of the A2B5 antigens, we performed lipidomic analyses on A2B5+/GFAP+ and A2B5−/GFAP+ cells from rat spinal cord. First, A2B5+/GFAP− progenitors were exposed to the leukemia inhibitory factor (LIF) or bone morphogenetic protein (BMP) to induce their differentiation to A2B5+/GFAP+ cells or A2B5−/GFAP+ astrocytes, respectively. The cells were then analyzed for changes in their phospholipid, sphingolipid or acyl chain profiles by mass spectrometry and gas chromatography. Compared to A2B5+/GFAP− progenitors, A2B5−/GFAP+ astrocytes contained higher amounts of ether phospholipids (especially the species containing arachidonic acid) and sphingomyelin, which may indicate characteristics of cellular differentiation and inability for multipotency. In comparison, principal component analyses revealed that the lipid composition of A2B5+/GFAP+ cells retained many of the characteristics of A2B5+/GFAP− progenitors, but their lipid profile was different from that of A2B5−/GFAP+ astrocytes. Thus, our study demonstrated that two GFAP+ cell populations have distinct lipid profiles with the A2B5+/GFAP+ cells sharing a phospholipid profile with progenitors rather than astrocytes. The progenitor cells may require regulated low levels of lipids known to mediate signaling functions in differentiated cells, and the precursor lipid profiles may serve as one measure of the differentiation capacity of a cell population.

Keywords

A2B5 antigen Astrocyte Glial fibrillary acidic protein Glial progenitor/precursor cell Lipidomics Mass spectrometry Phospholipid Sphingolipid 

Abbreviations

BMP

Bone morphogenetic protein

CERS2

Ceramide synthase 2

CNS

Central nervous system

CNTF

Ciliary neurotrophic factor

FA

Fatty acid

gp130

Membrane glycoprotein 130

GFAP

Glial fibrillary acidic protein

GlcCer

Glucosylceramide

GRP

Glial restricted precursor

GRP-LIF

GRP and LIF-stimulated A2B5+/GFAP+ cell

IL-6

Interleukin 6

JAK

Janus kinase

LIF

Leukemia inhibitory factor

MUFA

Monounsaturated fatty acid

PC

Phosphatidylcholine

PCA

Principal component analysis

PE

Phosphatidylethanolamine

PGE2

Prostaglandin E2

PI

Phosphatidylinositol

PL

Phospholipid

PS

Phosphatidylserine

PUFA

Polyunsaturated fatty acid

SFA

Saturated fatty acid

SIMCA

Soft independent modeling of class analogy

SL

Sphingolipid

SM

Sphingomyelin

STAT

Signal transducer and activator of transcription

Notes

Acknowledgments

We thank Agnès Viherä, Lea Armassalo, Tarja Grundström, Eliisa Kekäläinen, Aaro Miettinen, and Johanna Mäkelä for excellent technical assistance, the Molecular Imaging Unit of Biomedicum Helsinki for the use of their instrument and for assistance, and Dr. Masaaki Kitada for helpful comments on this research. This work was supported in part by a fellowship funding from Academy of Finland (No. 111261 to RK), grants from Japan Brain Foundation (YI), the Nakayama Foundation of Human Science (YI), and the Mizutani Foundation for Glycoscieince (150026 to YI).

References

  1. 1.
    Jayakumar AR, Tong XY, Curtis KM, Ruiz-Cordero R, Shamaladevi N, Abuzamel M, Johnstone J, Gaidosh G, Rama Rao KV, Norenberg MD (2014) Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies. J Neurochem 131:333–347CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rodnight RB, Gottfried C (2013) Morphological plasticity of rodent astroglia. J Neurochem 124:263–275CrossRefPubMedGoogle Scholar
  3. 3.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35CrossRefPubMedGoogle Scholar
  4. 4.
    Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, Kessaris N, Alvarez-Buylla A, Richardson WD, Rowitch DH (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337:358–362CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Eisenbarth GS, Walsh FS, Nirenberg M (1979) Monoclonal antibody to a plasma membrane antigen of neurons. Proc Natl Acad Sci USA 76:4913–4917CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kasai N, Yu RK (1983) The monoclonal antibody A2B5 is specific to ganglioside GQ1c. Brain Res 277:155–158CrossRefPubMedGoogle Scholar
  7. 7.
    Raff MC, Abney ER, Cohen J, Lindsay R, Noble M (1983) Two types of astrocytes in cultures of developing rat white matter: differences in morphology, surface gangliosides, and growth characteristics. J Neurosci 3:1289–1300PubMedGoogle Scholar
  8. 8.
    Saito M, Kitamura H, Sugiyama K (2001) The specificity of monoclonal antibody A2B5 to c-series gangliosides. J Neurochem 78:64–74CrossRefPubMedGoogle Scholar
  9. 9.
    Viljetic B, Labak I, Majic S, Stambuk A, Heffer M (2012) Distribution of mono-, di- and trisialo gangliosides in the brain of Actinopterygian fishes. Biochim Biophys Acta 1820:1437–1443CrossRefPubMedGoogle Scholar
  10. 10.
    Kishimoto N, Shimizu K, Sawamoto K (2012) Neuronal regeneration in a zebrafish model of adult brain injury. Dis Model Mech 5:200–209CrossRefPubMedGoogle Scholar
  11. 11.
    Itokazu Y, Yu RK (2014) Amyloid beta-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and Notch signaling. Mol Neurobiol 50:186–196CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ando S, Yu RK (1979) Isolation and characterization of two isomers of brain tetrasialogangliosides. J Biol Chem 254:12224–12229PubMedGoogle Scholar
  13. 13.
    Freischutz B, Saito M, Rahmann H, Yu RK (1994) Activities of five different sialyltransferases in fish and rat brains. J Neurochem 62:1965–1973CrossRefPubMedGoogle Scholar
  14. 14.
    Freischutz B, Saito M, Rahmann H, Yu RK (1995) Characterization of sialyltransferase-IV activity and its involvement in the c-pathway of brain ganglioside metabolism. J Neurochem 64:385–393CrossRefPubMedGoogle Scholar
  15. 15.
    Yu RK, Itokazu Y (2014) Glycolipid and glycoprotein expression during neural development. Adv Neurobiol 9:185–222CrossRefPubMedGoogle Scholar
  16. 16.
    Ngamukote S, Yanagisawa M, Ariga T, Ando S, Yu RK (2007) Developmental changes of glycosphingolipids and expression of glycogenes in mouse brains. J Neurochem 103:2327–2341CrossRefPubMedGoogle Scholar
  17. 17.
    Yu RK, Nakatani Y, Yanagisawa M (2009) The role of glycosphingolipid metabolism in the developing brain. J Lipid Res 50(Suppl):S440–S445PubMedPubMedCentralGoogle Scholar
  18. 18.
    Rao MS, Mayer-Proschel M (1997) Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. Dev Biol 188:48–63CrossRefPubMedGoogle Scholar
  19. 19.
    Bieberich E (2012) It’s a lipid’s world: bioactive lipid metabolism and signaling in neural stem cell differentiation. Neurochem Res 37:1208–1229CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    ten Grotenhuis E, Demel RA, Ponec M, Boer DR, van Miltenburg JC, Bouwstra JA (1996) Phase behavior of stratum corneum lipids in mixed Langmuir-Blodgett monolayers. Biophys J 71:1389–1399CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Grosch S, Schiffmann S, Geisslinger G (2012) Chain length-specific properties of ceramides. Prog Lipid Res 51:50–62CrossRefPubMedGoogle Scholar
  22. 22.
    Gross RE, Mehler MF, Mabie PC, Zang Z, Santschi L, Kessler JA (1996) Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 17:595–606CrossRefPubMedGoogle Scholar
  23. 23.
    Rajan P, McKay RD (1998) Multiple routes to astrocytic differentiation in the CNS. J Neurosci 18:3620–3629PubMedGoogle Scholar
  24. 24.
    Marks DL, Bittman R, Pagano RE (2008) Use of Bodipy-labeled sphingolipid and cholesterol analogs to examine membrane microdomains in cells. Histochem Cell Biol 130:819–832CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572CrossRefPubMedGoogle Scholar
  26. 26.
    Tajima N, Itokazu Y, Korpi ER, Somerharju P, Käkelä R (2011) Activity of BK(Ca) channel is modulated by membrane cholesterol content and association with Na+/K+-ATPase in human melanoma IGR39 cells. J Biol Chem 286:5624–5638CrossRefPubMedGoogle Scholar
  27. 27.
    Lee MY, Ryu JM, Lee SH, Park JH, Han HJ (2010) Lipid rafts play an important role for maintenance of embryonic stem cell self-renewal. J Lipid Res 51:2082–2089CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yanagisawa M, Nakamura K, Taga T (2004) Roles of lipid rafts in integrin-dependent adhesion and gp130 signalling pathway in mouse embryonic neural precursor cells. Genes Cells 9:801–809CrossRefPubMedGoogle Scholar
  29. 29.
    Yang C, Ji L, Yue W, Wang RY, Li YH, Xi JF, Xie XY, He LJ, Nan X, Pei XT (2010) Erythropoietin gene-modified conditioned medium of human mesenchymal cells promotes hematopoietic development from human embryonic stem cells. J Exp Hematol/Chin Assoc Pathophysiol 18:976–980Google Scholar
  30. 30.
    Bouffi C, Bony C, Courties G, Jorgensen C, Noel D (2010) IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS ONE 5:e14247CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bonaguidi MA, McGuire T, Hu M, Kan L, Samanta J, Kessler JA (2005) LIF and BMP signaling generate separate and discrete types of GFAP-expressing cells. Development 132:5503–5514CrossRefPubMedGoogle Scholar
  32. 32.
    Kang JX, Wan JB, He C (2013) Regulation of stem cell proliferation and differentiation by essential fatty acids and their metabolites. Stem Cells 32:1092–1098CrossRefGoogle Scholar
  33. 33.
    Doria ML, Cotrim Z, Macedo B, Simoes C, Domingues P, Helguero L, Domingues MR (2012) Lipidomic approach to identify patterns in phospholipid profiles and define class differences in mammary epithelial and breast cancer cells. Breast Cancer Res Treat 133:635–648CrossRefPubMedGoogle Scholar
  34. 34.
    Alexanian AR, Svendsen CN, Crowe MJ, Kurpad SN (2011) Transplantation of human glial-restricted neural precursors into injured spinal cord promotes functional and sensory recovery without causing allodynia. Cytotherapy 13:61–68CrossRefPubMedGoogle Scholar
  35. 35.
    Davies JE, Huang C, Proschel C, Noble M, Mayer-Proschel M, Davies SJ (2006) Astrocytes derived from glial-restricted precursors promote spinal cord repair. J Biol 5:7CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Davies JE, Proschel C, Zhang N, Noble M, Mayer-Proschel M, Davies SJ (2008) Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. J Biol 7:24CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Davies SJ, Shih CH, Noble M, Mayer-Proschel M, Davies JE, Proschel C (2011) Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS ONE 6:e17328CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Haas C, Fischer I (2013) Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. J Neurotrauma 30:1035–1052CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Haas C, Neuhuber B, Yamagami T, Rao M, Fischer I (2012) Phenotypic analysis of astrocytes derived from glial restricted precursors and their impact on axon regeneration. Exp Neurol 233:717–732CrossRefPubMedGoogle Scholar
  40. 40.
    Han SS, Liu Y, Tyler-Polsz C, Rao MS, Fischer I (2004) Transplantation of glial-restricted precursor cells into the adult spinal cord: survival, glial-specific differentiation, and preferential migration in white matter. Glia 45:1–16CrossRefPubMedGoogle Scholar
  41. 41.
    Hill CE, Proschel C, Noble M, Mayer-Proschel M, Gensel JC, Beattie MS, Bresnahan JC (2004) Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol 190:289–310CrossRefPubMedGoogle Scholar
  42. 42.
    Jin Y, Neuhuber B, Singh A, Bouyer J, Lepore A, Bonner J, Himes T, Campanelli JT, Fischer I (2011) Transplantation of human glial restricted progenitors and derived astrocytes into a contusion model of spinal cord injury. J Neurotrauma 28:579–594CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lepore AC, Neuhuber B, Connors TM, Han SS, Liu Y, Daniels MP, Rao MS, Fischer I (2006) Long-term fate of neural precursor cells following transplantation into developing and adult CNS. Neuroscience 139:513–530CrossRefPubMedGoogle Scholar
  44. 44.
    Porambo M, Phillips AW, Marx J, Ternes K, Arauz E, Pletnikov M, Wilson MA, Rothstein JD, Johnston MV, Fatemi A (2015) Transplanted glial restricted precursor cells improve neurobehavioral and neuropathological outcomes in a mouse model of neonatal white matter injury despite limited cell survival. Glia 63:452–465CrossRefPubMedGoogle Scholar
  45. 45.
    Walczak P, All AH, Rumpal N, Gorelik M, Kim H, Maybhate A, Agrawal G, Campanelli JT, Gilad AA, Kerr DA, Bulte JW (2011) Human glial-restricted progenitors survive, proliferate, and preserve electrophysiological function in rats with focal inflammatory spinal cord demyelination. Glia 59:499–510CrossRefPubMedGoogle Scholar
  46. 46.
    Rao MS, Noble M, Mayer-Proschel M (1998) A tripotential glial precursor cell is present in the developing spinal cord. Proc Natl Acad Sci USA 95:3996–4001CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Li H, Grumet M (2007) BMP and LIF signaling coordinately regulate lineage restriction of radial glia in the developing forebrain. Glia 55:24–35CrossRefPubMedGoogle Scholar
  48. 48.
    Noble M, Davies JE, Mayer-Proschel M, Proschel C, Davies SJ (2011) Precursor cell biology and the development of astrocyte transplantation therapies: lessons from spinal cord injury. Neurotherapeutics 8:677–693CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509PubMedGoogle Scholar
  50. 50.
    Hermansson M, Käkelä R, Berghäll M, Lehesjoki AE, Somerharju P, Lahtinen U (2005) Mass spectrometric analysis reveals changes in phospholipid, neutral sphingolipid and sulfatide molecular species in progressive epilepsy with mental retardation, EPMR, brain: a case study. J Neurochem 95:609–617CrossRefPubMedGoogle Scholar
  51. 51.
    Hermansson M, Uphoff A, Käkelä R, Somerharju P (2005) Automated quantitative analysis of complex lipidomes by liquid chromatography/mass spectrometry. Anal Chem 77:2166–2175CrossRefPubMedGoogle Scholar
  52. 52.
    Käkelä R, Somerharju P, Tyynelä J (2003) Analysis of phospholipid molecular species in brains from patients with infantile and juvenile neuronal-ceroid lipofuscinosis using liquid chromatography-electrospray ionization mass spectrometry. J Neurochem 84:1051–1065CrossRefPubMedGoogle Scholar
  53. 53.
    Kilpinen L, Tigistu-Sahle F, Oja S, Greco D, Parmar A, Saavalainen P, Nikkila J, Korhonen M, Lehenkari P, Käkelä R, Laitinen S (2013) Aging bone marrow mesenchymal stromal cells have altered membrane glycerophospholipid composition and functionality. J Lipid Res 54:622–635CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Koivusalo M, Haimi P, Heikinheimo L, Kostiainen R, Somerharju P (2001) Quantitative determination of phospholipid compositions by ESI-MS: effects of acyl chain length, unsaturation, and lipid concentration on instrument response. J Lipid Res 42:663–672PubMedGoogle Scholar
  55. 55.
    Brügger B, Erben G, Sandhoff R, Wieland FT, Lehmann WD (1997) Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry. Proc Natl Acad Sci USA 94:2339–2344CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sullards MC, Merrill AH Jr (2001) Analysis of sphingosine 1-phosphate, ceramides, and other bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Sci STKE 67:l1Google Scholar
  57. 57.
    Haimi P, Uphoff A, Hermansson M, Somerharju P (2006) Software tools for analysis of mass spectrometric lipidome data. Anal Chem 78:8324–8331CrossRefPubMedGoogle Scholar
  58. 58.
    Käkelä R, Käkelä A, Kahle S, Becker PH, Kelly A, Furness RW (2005) Fatty acid signatures in plasma of captive herring gulls as indicators of demersal or pelagic fish diet. Mar Ecol Prog Ser 293:191–200CrossRefGoogle Scholar
  59. 59.
    Kvalheim OM, Karstang TV (1987) A General-purpose program for multivariate data-analysis. Chemometr Intell Lab 2:235–237CrossRefGoogle Scholar
  60. 60.
    Prinetti A, Chigorno V, Tettamanti G, Sonnino S (2000) Sphingolipid-enriched membrane domains from rat cerebellar granule cells differentiated in culture. A compositional study. J Biol Chem 275:11658–11665CrossRefPubMedGoogle Scholar
  61. 61.
    Pike LJ, Han X, Chung KN, Gross RW (2002) Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of caveolin-1 expression: a quantitative electrospray ionization/mass spectrometric analysis. Biochemistry 41:2075–2088CrossRefPubMedGoogle Scholar
  62. 62.
    Chilton FH, Fonteh AN, Surette ME, Triggiani M, Winkler JD (1996) Control of arachidonate levels within inflammatory cells. Biochim Biophys Acta 1299:1–15CrossRefPubMedGoogle Scholar
  63. 63.
    Diez E, Chilton FH, Stroup G, Mayer RJ, Winkler JD, Fonteh AN (1994) Fatty acid and phospholipid selectivity of different phospholipase A2 enzymes studied by using a mammalian membrane as substrate. Biochem J 301(Pt 3):721–726CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sakayori N, Maekawa M, Numayama-Tsuruta K, Katura T, Moriya T, Osumi N (2011) Distinctive effects of arachidonic acid and docosahexaenoic acid on neural stem/progenitor cells. Genes Cells 16:778–790CrossRefPubMedGoogle Scholar
  65. 65.
    Mizutani Y, Kihara A, Igarashi Y (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390:263–271CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Adachi T, Takanaga H, Kunimoto M, Asou H (2005) Influence of LIF and BMP-2 on differentiation and development of glial cells in primary cultures of embryonic rat cerebral hemisphere. J Neurosci Res 79:608–615CrossRefPubMedGoogle Scholar
  67. 67.
    Mayer M, Bhakoo K, Noble M (1994) Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development 120:143–153PubMedGoogle Scholar
  68. 68.
    Mabie PC, Mehler MF, Kessler JA (1999) Multiple roles of bone morphogenetic protein signaling in the regulation of cortical cell number and phenotype. J Neurosci 19:7077–7088PubMedGoogle Scholar
  69. 69.
    Yung SY, Gokhan S, Jurcsak J, Molero AE, Abrajano JJ, Mehler MF (2002) Differential modulation of BMP signaling promotes the elaboration of cerebral cortical GABAergic neurons or oligodendrocytes from a common sonic hedgehog-responsive ventral forebrain progenitor species. Proc Natl Acad Sci USA 99:16273–16278CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Gieselmann V, Sandhoff K, Willecke K (2009) Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem 284:33549–33560CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Fukuda S, Taga T (2005) Cell fate determination regulated by a transcriptional signal network in the developing mouse brain. Anat Sci Int 80:12–18CrossRefPubMedGoogle Scholar
  72. 72.
    Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284:479–482CrossRefPubMedGoogle Scholar
  73. 73.
    Kondo T, Raff M (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289:1754–1757CrossRefPubMedGoogle Scholar
  74. 74.
    Sjövall P, Lausmaa J, Johansson B (2004) Mass spectrometric imaging of lipids in brain tissue. Anal Chem 76:4271–4278CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yutaka Itokazu
    • 1
    • 2
    • 3
    • 4
  • Nobuyoshi Tajima
    • 2
    • 5
  • Laura Kerosuo
    • 2
    • 6
  • Pentti Somerharju
    • 2
  • Hannu Sariola
    • 2
  • Robert K. Yu
    • 3
    • 4
  • Reijo Käkelä
    • 1
    • 2
    Email author
  1. 1.Department of BiosciencesUniversity of HelsinkiHelsinkiFinland
  2. 2.Institute of Biomedicine, Department of Biochemistry and Developmental BiologyUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of Neuroscience and Regenerative Medicine, Medical College of GeorgiaAugusta UniversityAugustaUSA
  4. 4.Charlie Norwood VA Medical CenterAugustaUSA
  5. 5.Department of PhysiologyKanazawa Medical UniversityIshikawaJapan
  6. 6.Division of Biology and Biological EngineeringCalifornia Institute of TechnologyPasadenaUSA

Personalised recommendations