In vivo conversion of rat astrocytes into neuronal cells through neural stem cells in injured spinal cord with a single zinc-finger transcription factor.
Adult astrocyte
Conversion
In vivo reprogramming
Neural stem cells
Reprogramming
Spinal cord injury
Zfp521
Journal
Stem cell research & therapy
ISSN: 1757-6512
Titre abrégé: Stem Cell Res Ther
Pays: England
ID NLM: 101527581
Informations de publication
Date de publication:
16 12 2019
16 12 2019
Historique:
received:
19
06
2019
accepted:
09
10
2019
revised:
23
09
2019
entrez:
18
12
2019
pubmed:
18
12
2019
medline:
4
9
2020
Statut:
epublish
Résumé
Spinal cord injury (SCI) results in glial scar formation and irreversible neuronal loss, which finally leads to functional impairments and long-term disability. Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs). However, it remains unclear whether treatment with Zfp521 also affects endogenous astrocytes, thus promoting further functional recovery following SCI. Rat astrocytes were transdifferentiated into neural stem cells in vitro by ZFP521 or Sox2. Then, ZFP521 was applied to the spinal cord injury site of a rat. Transduction, real-time PCR, immunohistofluorescence, and function assessments were performed at 6 weeks post-transduction to evaluate improvement and in vivo lineage reprogramming of astrocytes. Here, we show that Zfp521 is more efficient in reprogramming cultured astrocytes compared with Sox2. In the injured spinal cord of an adult rat, resident astrocytes can be reprogrammed into neurons through a progenitor stage by Zfp521. Importantly, this treatment improves the functional abilities of the rats as evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and further by calculation of its subscores. There was enhanced locomotor activity in the hind limbs, step length, toe spread, foot length, and paw area. In addition, motor evoked potential recordings demonstrated the functional integrity of the spinal cord. These results have indicated that the generation of iNSCs or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair.
Sections du résumé
BACKGROUND
Spinal cord injury (SCI) results in glial scar formation and irreversible neuronal loss, which finally leads to functional impairments and long-term disability. Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs). However, it remains unclear whether treatment with Zfp521 also affects endogenous astrocytes, thus promoting further functional recovery following SCI.
METHODS
Rat astrocytes were transdifferentiated into neural stem cells in vitro by ZFP521 or Sox2. Then, ZFP521 was applied to the spinal cord injury site of a rat. Transduction, real-time PCR, immunohistofluorescence, and function assessments were performed at 6 weeks post-transduction to evaluate improvement and in vivo lineage reprogramming of astrocytes.
RESULTS
Here, we show that Zfp521 is more efficient in reprogramming cultured astrocytes compared with Sox2. In the injured spinal cord of an adult rat, resident astrocytes can be reprogrammed into neurons through a progenitor stage by Zfp521. Importantly, this treatment improves the functional abilities of the rats as evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and further by calculation of its subscores. There was enhanced locomotor activity in the hind limbs, step length, toe spread, foot length, and paw area. In addition, motor evoked potential recordings demonstrated the functional integrity of the spinal cord.
CONCLUSIONS
These results have indicated that the generation of iNSCs or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair.
Identifiants
pubmed: 31842989
doi: 10.1186/s13287-019-1448-x
pii: 10.1186/s13287-019-1448-x
pmc: PMC6916443
doi:
Substances chimiques
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
380Références
PLoS One. 2015 Oct 01;10(10):e0139335
pubmed: 26426529
J Neurotrauma. 2004 Apr;21(4):395-404
pubmed: 15115589
Nature. 2011 Feb 24;470(7335):503-9
pubmed: 21326203
Cytotherapy. 2009;11(5):618-30
pubmed: 19548142
Nat Commun. 2014 Feb 25;5:3338
pubmed: 24569435
J Neurotrauma. 2001 Feb;18(2):203-15
pubmed: 11229712
Biomaterials. 2017 Jul;134:13-21
pubmed: 28453954
Nat Cell Biol. 2015 Mar;17(3):204-11
pubmed: 25720960
Stem Cells Transl Med. 2018 Nov;7(11):806-818
pubmed: 30085415
Stem Cells Dev. 2012 Jul 1;21(10):1794-802
pubmed: 21970342
Cell Stem Cell. 2014 Feb 6;14(2):188-202
pubmed: 24360883
Cell Transplant. 2012;21(5):827-43
pubmed: 21944670
J Neurosci Methods. 1997 Jul 18;75(1):49-54
pubmed: 9262143
J Neurotrauma. 2016 May 15;33(10):907-16
pubmed: 26560177
J Physiol. 2016 Jul 1;594(13):3533-8
pubmed: 26876753
Cell Rep. 2015 Jul 21;12(3):474-81
pubmed: 26166567
Stem Cell Reports. 2016 Apr 12;6(4):539-551
pubmed: 27052315
Cell Transplant. 2015;24(1):115-31
pubmed: 24152553
Cell Transplant. 2013;22(9):1591-612
pubmed: 24007776
Turk Neurosurg. 2016;26(1):127-39
pubmed: 26768879
J Neurotrauma. 1995 Feb;12(1):1-21
pubmed: 7783230
Exp Neurol. 2003 Jun;181(2):115-29
pubmed: 12781986
Exp Neurol. 1999 Aug;158(2):351-65
pubmed: 10415142
Antioxid Redox Signal. 2018 Sep 20;29(9):864-879
pubmed: 28762752
Nat Rev Neurosci. 2006 Aug;7(8):628-43
pubmed: 16858391
PLoS One. 2015 Jun 01;10(6):e0127878
pubmed: 26030913
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3581-6
pubmed: 18299565
J Clin Invest. 2017 Sep 1;127(9):3259-3270
pubmed: 28737515
Stem Cell Reports. 2015 May 12;4(5):780-94
pubmed: 25921813
Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):7038-43
pubmed: 23530235
Exp Neurol. 2010 Aug;224(2):429-37
pubmed: 20488178
Nature. 2016 Apr 14;532(7598):195-200
pubmed: 27027288
Transpl Immunol. 2005 Dec;15(2):131-42
pubmed: 16412957
J Cell Physiol. 2019 Aug;234(10):18697-18706
pubmed: 30912162
PLoS One. 2018 Sep 13;13(9):e0203785
pubmed: 30212518
Exp Neurol. 2014 Mar;253:197-207
pubmed: 24424280
Brain Res. 2018 Nov 15;1699:19-33
pubmed: 29883625
Curr Opin Genet Dev. 2017 Oct;46:132-140
pubmed: 28779646
Stem Cell Reports. 2015 Sep 8;5(3):405-18
pubmed: 26321141
Nat Cell Biol. 2013 Oct;15(10):1164-75
pubmed: 24056302
Exp Neurol. 2007 Jun;205(2):396-406
pubmed: 17433295
J Neurosci. 2012 Jun 6;32(23):7926-40
pubmed: 22674268
Nat Rev Neurosci. 2006 Aug;7(8):644-53
pubmed: 16858392
Stem Cell Reports. 2018 Dec 11;11(6):1433-1448
pubmed: 30472009
Stem Cells Dev. 2018 Jun 1;27(11):736-744
pubmed: 29635978