pp 1–6 | Cite as

Genetic conversion of proliferative astroglia into neurons after cerebral ischemia: a new therapeutic tool for the aged brain?

  • Aurel Popa-WagnerEmail author
  • Dirk Hermann
  • Andrei Gresita
Review Article


Ischemic stroke represents the 2nd leading cause of death worldwide and the leading cause for long-term disabilities, for which no cure exists. After stroke, neurons are frequently lost in the infarct core. On the other hand, other cells such as astrocytes become reactive and proliferative, disrupting the neurovascular unit in the lesioned area, especially in the aged brain. Therefore, restoring the balance between neurons and nonneuronal cells within the perilesional area is crucial for post stroke recovery. In addition, the aged post stroke brain mounts a fulminant proliferative astroglial response leading to the buildup of gliotic scars that prevent neural regeneration. Therefore, “melting” glial scars has been attempted for decades, albeit with little success. Alternative strategies include transforming inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth by genetic conversion of astrocytes into neurons. The latter idea has gained momentum following the discovery that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming nonneuronal cells into neurons. This exciting new technology emerged as a new approach to circumvent cell transplantation for stroke therapy. However, the potential of this new methodology has not been yet tested to improve restoration of structure and function in the hostile environment caused by the fulminant inflammatory reaction in the brains of aged animals.


Aging Cerebral ischemia Therapy Glial scar Genetic conversion 


Funding information

This work was supported by the EU Framework Programme for Research and Innovation, Horizont 2020, project number 667302 to APW, and UEFISCDI, project numbers PN-III-P4-ID-PCE-2016-0340 to DH and PN-III-P2-2.1-PED-2016-1013 and PN-III-P4-ID-PCE-2016-0215 to APW.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8(9):963–970. Google Scholar
  2. Ay H, Koroshetz WJ, Vangel M, Benner T, Melinosky C, Zhu M et al (2005) Conversion of ischemic brain tissue into infarction increases with age. Stroke 36(12):2632–2636Google Scholar
  3. Balseanu AT, Buga AM, Catalin B, Wagner DC, Boltze J et al (2014) Multimodal approaches for regenerative stroke therapies: combination of granulocyte colony-stimulating factor with bone marrow mesenchymal stem cells is not superior to G-CSF alone. Front Aging Neurosci 6:130. Google Scholar
  4. Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H et al (2013) Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497(7449):369–373. Google Scholar
  5. Berninger B, Costa MR, Koch U, Schroeder T, Sutor B, Grothe B, Götz M (2007) Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. J Neurosci 27(32):8654–8664. Google Scholar
  6. Boltze J, Arnold A, Walczak P, Jolkkonen J, Cui L, Wagner DC (2015) The dark side of the force – constraints and complications of cell therapies for stroke. Front Neurol 6:155. Google Scholar
  7. Buga AM, Di Napoli M, Popa-Wagner A (2013) Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation. Biogerontology 14(6):651–662. Google Scholar
  8. Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81(2):229–248. Google Scholar
  9. Darsalia V, Heldmann U, Lindvall O, Kokaia Z (2005) Stroke-induced neurogenesis in aged brain. Stroke 36(8):1790–1795. Google Scholar
  10. Duan CL, Liu CW, Shen SW et al (2015) Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. Glia 63(9):1660–1670. Google Scholar
  11. Faiz M, Sachewsky N, Gascón S, Bang KW, Morshead CM, Nagy A (2015) Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell 17(5):624–634. Google Scholar
  12. Ferreira AC, Da Mesquita S, Sousa JC, Correia-Neves M, Sousa N, Palha JA, Marques F (2015) From the periphery to the brain: lipocalin-2, a friend or foe? Prog Neurobiol 131:120–136. Google Scholar
  13. Ferri AL, Cavallaro M, Braida D, Di Cristofano A, Canta A, Vezzani A et al (2004) Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 131(15):3805–3819. Google Scholar
  14. Fu Y, Liu Q, Anrather J, Shi FD (2015) Immune interventions in stroke. Nat Rev Neurol 11(9):524–535. Google Scholar
  15. Gao X, Wang X, Xiong W, Chen J (2016) In vivo reprogramming reactive glia into iPSCs to produce new neurons in the cortex following traumatic brain injury. Sci Rep 6:22490. Google Scholar
  16. Gascón S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D et al (2016) Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming. Cell Stem Cell 18(3):396–409. Google Scholar
  17. Ge WP, Miyawaki A, Gage FH, Jan YN, Jan LY (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484(7394):376–380. Google Scholar
  18. Grande A, Sumiyoshi K, López-Juárez A et al (2013) Environmental impact on direct neuronal reprogramming in vivo in the adult brain. Nat Commun 4:2373. Google Scholar
  19. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G (2013) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 14(2):188–202. Google Scholar
  20. Heinrich C, Blum R, Gascón S et al (2010) Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biol 8(5):e1000373. Google Scholar
  21. Hermann DM, Popa-Wagner A, Kleinschnitz C, Doeppner TR (2019) Animal models of ischemic stroke and their impact on drug discovery. Expert Opin Drug Discovery 14(3):315–326. Google Scholar
  22. Hou SW, Wang YQ, Xu M, Shen DH, Wang JJ, Huang F, Yu Z, Sun FY (2008) Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke 39(10):2837–2844. Google Scholar
  23. Jin KL, Wang XM, Xie L, Mao XO, Zhu W, Wang Y, … Greenberg DA (2006) Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A 103(35):13198–13202.
  24. Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7(9):a018812. Google Scholar
  25. Koprivica V, Cho KS, Park JB, Yiu G, Atwal J, Gore B, Kim JA, Lin E, Tessier-Lavigne M, Chen DF et al (2005) EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310(5745):106–110. Google Scholar
  26. Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184. Google Scholar
  27. Magnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EM, Lindvall O, Kokaia Z, Frisén J (2014) A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 346(6206):237–241. Google Scholar
  28. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4):687–702. Google Scholar
  29. Mo JL, Liu Q, Kou ZW et al (2018) MicroRNA-365 modulates astrocyte conversion into neuron in adult rat brain after stroke by targeting Pax6. Glia 66(7):1346–1362. Google Scholar
  30. Nadareishvili Z, Hallenbeck J (2003) Neuronal regeneration after stroke. N Engl J Med 348(23):2355–2356. Google Scholar
  31. Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang CL (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nat Cell Biol 15(10):1164–1175. Google Scholar
  32. Okano H, Yamanaka S (2014) iPS cell technologies: significance and applications to CNS regeneration and disease. Mol Brain 7:22. Google Scholar
  33. Pereira M, Birtele M, Shrigley S et al (2017) Direct reprogramming of resident NG2 glia into neurons with properties of fast-spiking parvalbumin-containing interneurons. Stem Cell Rep 9(3):742–751. Google Scholar
  34. Popa-Wagner A, Carmichael ST, Kokaia Z, Walker LC (2007) The response of the aged brain to stroke: too much, too soon? Curr Neurovasc Res 4:216–277. Google Scholar
  35. Popa-Wagner A, Buga A-M, Doeppner TR, Hermann DM (2014) Stem cell therapies in preclinical models of stroke associated with aging. Front Cell Neurosci 8:347. Google Scholar
  36. Robel S, Berninger B, Götz M (2011) The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci 12(2):88–104. Google Scholar
  37. Roger VL, Go AS, Lloyd-Jones DM et al (2012) 2012. Heart disease and stroke statistics--2012 update: a report from the American Heart Association [published correction appears in Circulation. 2012 Jun 5;125(22):e1002]. Circulation 125(1):e2–e220. Google Scholar
  38. Sandu RE, Buga AM, Balseanu AT, Moldovan M, Popa-Wagner A (2016) Twenty four hours hypothermia has temporary efficacy in reducing brain infarction and inflammation in aged rats. Neurobiol Aging 38:127–140. Google Scholar
  39. Shimada IS, LeComte MD, Granger JC, Quinlan NJ, Spees JL (2012) Self-renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. J Neurosci 32(23):7926–7940. Google Scholar
  40. Silver J (2016) The glial scar is more than just astrocytes. Exp Neurol 286:147–149. Google Scholar
  41. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156. Google Scholar
  42. Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S et al (2013) Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. [corrected]. Cell Stem Cell 12(4):426–439. Google Scholar
  43. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35. Google Scholar
  44. Stroke Therapy Academic Industry Roundtable (STAIR) (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30(12):2752–2758 ReviewGoogle Scholar
  45. Sun X, Zhang QW, Xu M, Guo JJ, Shen SW, Wang YQ, Sun FY (2012) New striatal neurons form projections to substantia nigra in adult rat brain after stroke. Neurobiol Dis 45(1):601–609. Google Scholar
  46. Tatarishvili J, Oki K, Buga AM, Popa-Wagner A, Brüstle O, Lindvall O, Kokaia Z (2014) Human induced pluripotent stem cells improve recovery in stroke-injured aged rats. Restor Neurol Neurosci 32(4):547–558. Google Scholar
  47. Torper O, Pfisterer U, Wolf DA et al (2013) Generation of induced neurons via direct conversion in vivo. Proc Natl Acad Sci U S A 110(17):7038–7043. Google Scholar
  48. Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H et al (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337(6092):358–362. Google Scholar
  49. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041. Google Scholar
  50. Wang L, Chopp M, Zhang RL, Zhang L, Letourneau Y, Feng YF, Jiang A, Morris DC, Zhang ZG (2009) The Notch pathway mediates expansion of a progenitor pool and neuronal differentiation in adult neural progenitor cells after stroke. Neuroscience 158(4):1356–1363. Google Scholar
  51. Wang Y, Kong QJ, Sun JC, Yang Y, Wang HB, Zhang Q, Shi JG (2018) Lentivirus-mediated silencing of the CTGF gene suppresses the formation of glial scar tissue in a rat model of spinal cord injury. Spine J 18(1):164–172. Google Scholar
  52. Zhang QW, Deng XX, Sun X, Xu JX, Sun FY (2013) Exercise promotes axon regeneration of newborn striatonigral and corticonigral projection neurons in rats after ischemic stroke. PLoS One 8(11):e80139. Google Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Aurel Popa-Wagner
    • 1
    • 2
    Email author
  • Dirk Hermann
    • 2
  • Andrei Gresita
    • 1
  1. 1.Center of Clinical and Experimental MedicineUniversity of Medicine and PharmacyCraiovaRomania
  2. 2.Vascular Neurology, Dementia and Ageing Research, Department of Neurology, University of Duisburg-EssenUniversity Hospital EssenEssenGermany

Personalised recommendations