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Different Temporal Patterns in the Expressions of Bone Morphogenetic Proteins and Noggin During Astroglial Scar Formation After Ischemic Stroke

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Abstract

Bone morphogenetic proteins (BMPs) and their antagonists have roles in scar formation and regeneration after central nervous system injuries. However, temporal changes in their expression during astroglial scar formation in the ischemic brain are unknown. Here, we examined protein levels of BMP2, BMP7, and their antagonist noggin in the ischemic brain up to 4 weeks after experimental stroke in mice. BMP2 and BMP7 levels were increased from 1 to 4 weeks in the ischemic brain, and their expression was associated with astrogliosis. BMP7 expression was more intense and co-localized in reactive astrocytes in the ischemic subcortex at 1 week. Noggin expression began to increase after 2 weeks and was further increased at 4 weeks only in the ischemic subcortex, but the intensity was weak compared to the intensity of BMPs. Noggin was co-localized mainly in activated microglia. These findings show that expression of BMPs and noggin differed over time, in intensity and in types of cell, and suggest that BMPs and noggin have different roles in the processes of glial scar formation and neurorestoration in the ischemic brain.

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Abbreviations

BMPs:

Bone morphogenetic proteins

CBF:

Cerebral blood flow

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium binding adaptor molecule 1

MCAO:

Middle cerebral artery occlusion

OPC:

Oligodendrocyte precursor cell

PLSD:

Protected least significant difference

TBS:

Tris-buffered saline

References

  • Ara J, See J, Mamontov P, Hahn A, Bannerman P, Pleasure D, Grinspan JB (2008) Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitis. J Neurosci Res 86:125–135

    Article  PubMed  CAS  Google Scholar 

  • Bessa PC, Casal M, Reis RL (2008a) Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med 2:81–96

    Article  PubMed  CAS  Google Scholar 

  • Bessa PC, Casal M, Reis RL (2008b) Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts). J Tissue Eng Regen Med 2:1–13

    Article  PubMed  CAS  Google Scholar 

  • Bonaguidi MA, Peng CY, McGuire T, Falciglia G, Gobeske KT, Czeisler C, Kessler JA (2008) Noggin expands neural stem cells in the adult hippocampus. J Neurosci 28:9194–9204

    Article  PubMed  CAS  Google Scholar 

  • Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308

    Article  PubMed  CAS  Google Scholar 

  • Chang CF, Lin SZ, Chiang YH, Morales M, Chou J, Lein P, Chen HL, Hoffer BJ, Wang Y (2003) Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 34:558–564

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Swanson RA (2003) Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149

    Article  PubMed  Google Scholar 

  • Cheng X, Wang Y, He Q, Qiu M, Whittemore SR, Cao Q (2007) Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells. Stem Cells 25:3204–3214

    Article  PubMed  CAS  Google Scholar 

  • Chou J, Harvey BK, Chang CF, Shen H, Morales M, Wang Y (2006) Neuroregenerative effects of BMP7 after stroke in rats. J Neurol Sci 240:21–29

    Article  PubMed  CAS  Google Scholar 

  • Cramer SC (2008a) Repairing the human brain after stroke. II. Restorative therapies. Ann Neurol 63:549–560

    Article  PubMed  Google Scholar 

  • Cramer SC (2008b) Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann Neurol 63:272–287

    Article  PubMed  Google Scholar 

  • Duggal N, Schmidt-Kastner R, Hakim AM (1997) Nestin expression in reactive astrocytes following focal cerebral ischemia in rats. Brain Res 768:1–9

    Article  PubMed  CAS  Google Scholar 

  • Fuller ML, DeChant AK, Rothstein B, Caprariello A, Wang R, Hall AK, Miller RH (2007) Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Ann Neurol 62:288–300

    Article  PubMed  CAS  Google Scholar 

  • Hampton DW, Asher RA, Kondo T, Steeves JD, Ramer MS, Fawcett JW (2007) A potential role for bone morphogenetic protein signalling in glial cell fate determination following adult central nervous system injury in vivo. Eur J Neurosci 26:3024–3035

    Article  PubMed  Google Scholar 

  • Harvey BK, Hoffer BJ, Wang Y (2005) Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol Ther 105:113–125

    Article  PubMed  CAS  Google Scholar 

  • Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y (2001) Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 32:1208–1215

    Article  PubMed  CAS  Google Scholar 

  • Jones TA, Schallert T (1994) Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci 14:2140–2152

    PubMed  CAS  Google Scholar 

  • Jordan J, Bottner M, Schluesener HJ, Unsicker K, Krieglstein K (1997) Bone morphogenetic proteins: neurotrophic roles for midbrain dopaminergic neurons and implications of astroglial cells. Eur J Neurosci 9:1699–1709

    Article  PubMed  CAS  Google Scholar 

  • Kanakaris NK, Calori GM, Verdonk R, Burssens P, De Biase P, Capanna R, Vangosa LB, Cherubino P, Baldo F, Ristiniemi J, Kontakis G, Giannoudis PV (2008) Application of BMP-7 to tibial non-unions: a 3-year multicenter experience. Injury 39(Suppl 2):S83–S90

    Article  PubMed  Google Scholar 

  • Karaoglan A, Akdemir O, Barut S, Kokturk S, Uzun H, Tasyurekli M, Colak A (2008) The effects of resveratrol on vasospasm after experimental subarachnoidal hemorrhage in rats. Surg Neurol 70:337–343

    Article  PubMed  Google Scholar 

  • Kawamata T, Ren J, Chan TC, Charette M, Finklestein SP (1998) Intracisternal osteogenic protein-1 enhances functional recovery following focal stroke. Neuroreport 9:1441–1445

    Article  PubMed  CAS  Google Scholar 

  • Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD, McCullough LD (2004) Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol 187:94–104

    Article  PubMed  Google Scholar 

  • Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, Nodin C, Stahlberg A, Aprico K, Larsson K, Yabe T, Moons L, Fotheringham A, Davies I, Carmeliet P, Schwartz JP, Pekna M, Kubista M, Blomstrand F, Maragakis N, Nilsson M, Pekny M (2008) Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 28:468–481

    Article  PubMed  Google Scholar 

  • Lin RC, Matesic DF, Marvin M, McKay RD, Brustle O (1995) Re-expression of the intermediate filament nestin in reactive astrocytes. Neurobiol Dis 2:79–85

    Article  PubMed  CAS  Google Scholar 

  • Lin SZ, Hoffer BJ, Kaplan P, Wang Y (1999) Osteogenic protein-1 protects against cerebral infarction induced by MCA ligation in adult rats. Stroke 30:126–133

    Article  PubMed  CAS  Google Scholar 

  • Liu A, Niswander LA (2005) Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci 6:945–954

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Belayev L, Zhao W, Busto R, Saul I, Alonso O, Ginsberg MD (2001) The effect of bone morphogenetic protein-7 (BMP-7) on functional recovery, local cerebral glucose utilization and blood flow after transient focal cerebral ischemia in rats. Brain Res 905:81–90

    Article  PubMed  CAS  Google Scholar 

  • Mabie PC, Mehler MF, Marmur R, Papavasiliou A, Song Q, Kessler JA (1997) Bone morphogenetic proteins induce astroglial differentiation of oligodendroglial–astroglial progenitor cells. J Neurosci 17:4112–4120

    PubMed  CAS  Google Scholar 

  • Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

    Article  PubMed  CAS  Google Scholar 

  • Matsuura I, Taniguchi J, Hata K, Saeki N, Yamashita T (2008) BMP inhibition enhances axonal growth and functional recovery after spinal cord injury. J Neurochem 105:1471–1479

    Article  PubMed  CAS  Google Scholar 

  • McKeon RJ, Hoke A, Silver J (1995) Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp Neurol 136:32–43

    Article  PubMed  CAS  Google Scholar 

  • Mikawa S, Sato K (2011) Noggin expression in the adult rat brain. Neuroscience 184:38–53

    Article  PubMed  CAS  Google Scholar 

  • Nudo RJ, Wise BM, SiFuentes F, Milliken GW (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272:1791–1794

    Article  PubMed  CAS  Google Scholar 

  • Peretto P, Dati C, De Marchis S, Kim HH, Ukhanova M, Fasolo A, Margolis FL (2004) Expression of the secreted factors noggin and bone morphogenetic proteins in the subependymal layer and olfactory bulb of the adult mouse brain. Neuroscience 128:685–696

    Article  PubMed  CAS  Google Scholar 

  • Ren J, Kaplan PL, Charette MF, Speller H, Finklestein SP (2000) Time window of intracisternal osteogenic protein-1 in enhancing functional recovery after stroke. Neuropharmacology 39:860–865

    Article  PubMed  CAS  Google Scholar 

  • Roitbak T, Sykova E (1999) Diffusion barriers evoked in the rat cortex by reactive astrogliosis. Glia 28:40–48

    Article  PubMed  CAS  Google Scholar 

  • Rolls A, Shechter R, Schwartz M (2009) The bright side of the glial scar in CNS repair. Nat Rev Neurosci 10:235–241

    Article  PubMed  CAS  Google Scholar 

  • Samanta J, Alden T, Gobeske K, Kan L, Kessler JA (2010) Noggin protects against ischemic brain injury in rodents. Stroke 41:357–362

    Article  PubMed  CAS  Google Scholar 

  • Setoguchi T, Yone K, Matsuoka E, Takenouchi H, Nakashima K, Sakou T, Komiya S, Izumo S (2001) Traumatic injury-induced BMP7 expression in the adult rat spinal cord. Brain Res 921:219–225

    Article  PubMed  CAS  Google Scholar 

  • Shen CC, Yang YC, Chiao MT, Cheng WY, Tsuei YS, Ko JL (2010) Characterization of endogenous neural progenitor cells after experimental ischemic stroke. Curr Neurovasc Res 7:6–14

    Article  PubMed  CAS  Google Scholar 

  • Shin JA, Park EM, Choi JS, Seo SM, Kang JL, Lee KE, Cho S (2009) Ischemic preconditioning-induced neuroprotection is associated with differential expression of IL-1beta and IL-1 receptor antagonist in the ischemic cortex. J Neuroimmunol 217:14–19

    Article  PubMed  CAS  Google Scholar 

  • Stichel CC, Muller HW (1998) The CNS lesion scar: new vistas on an old regeneration barrier. Cell Tissue Res 294:1–9

    Article  PubMed  CAS  Google Scholar 

  • Withers GS, Higgins D, Charette M, Banker G (2000) Bone morphogenetic protein-7 enhances dendritic growth and receptivity to innervation in cultured hippocampal neurons. Eur J Neurosci 12:106–116

    Article  PubMed  CAS  Google Scholar 

  • Xiao Q, Du Y, Wu W, Yip HK (2010) Bone morphogenetic proteins mediate cellular response and, together with Noggin, regulate astrocyte differentiation after spinal cord injury. Exp Neurol 221:353–366

    Article  PubMed  CAS  Google Scholar 

  • Zaleska MM, Mercado ML, Chavez J, Feuerstein GZ, Pangalos MN, Wood A (2009) The development of stroke therapeutics: promising mechanisms and translational challenges. Neuropharmacology 56:329–341

    Article  PubMed  CAS  Google Scholar 

  • Zimmerman LB, De Jesus-Escobar JM, Harland RM (1996) The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86:599–606

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0011353 to E.M.P. and 2010-0029353 to J.L.K.).

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The authors declare that they have no conflict of interest.

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Correspondence to Eun-Mi Park.

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Shin, J.A., Kang, J.L., Lee, KE. et al. Different Temporal Patterns in the Expressions of Bone Morphogenetic Proteins and Noggin During Astroglial Scar Formation After Ischemic Stroke. Cell Mol Neurobiol 32, 587–597 (2012). https://doi.org/10.1007/s10571-012-9806-6

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