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Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis

Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis
Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis
The generation of new oligodendrocytes is essential for adult brain repair in diseases such as multiple sclerosis. We previously identified the multifunctional p57kip2 protein as a negative regulator of myelinating glial cell differentiation and as an intrinsic switch of glial fate decision in adult neural stem cells (aNSCs). In oligodendroglial precursor cells (OPCs), p57kip2 protein nuclear exclusion was recently found to be rate limiting for differentiation to proceed. Furthermore, stimulation with mesenchymal stem cell (MSC)-derived factors enhanced oligodendrogenesis by yet unknown mechanisms. To elucidate this instructive interaction, we investigated to what degree MSC secreted factors are species dependent, whether hippocampal aNSCs respond equally well to such stimuli, whether apart from oligodendroglial differentiation also tissue integration and axonal wrapping can be promoted and whether the oligodendrogenic effect involved subcellular translocation of p57kip2. We found that CC1 positive oligodendrocytes within the hilus express nuclear p57kip2 protein and that MSC dependent stimulation of cultured hippocampal aNSCs was not accompanied by nuclear p57kip2 exclusion as observed for parenchymal OPCs after spontaneous differentiation. Stimulation with human MSC factors was observed to equally promote rat stem cell oligodendrogenesis, axonal wrapping and tissue integration. As forced nuclear shuttling of p57kip2 led to decreased CNPase- but elevated GFAP expression levels, this indicates heterogenic oligodendroglial mechanisms occurring between OPCs and aNSCs. We also show for the first time that dominant pro-oligodendroglial factors derived from human fetal MSCs can instruct human induced pluripotent stem cell-derived NSCs to differentiate into O4 positive oligodendrocytes.
0894-1491
145-160
Jadasz, Janusz J.
717deca1-4be6-4b99-bf6f-078158e612d2
Tepe, Lena
fca6279f-ccde-489d-becd-6fdfe5b0747a
Beyer, Felix
50711ff0-bd57-4b2f-a5e1-c34f3519b185
Samper Agrelo, Iria
8df23a3c-3c10-423b-817f-2ed5bbdeba89
Akkermann, Rainer
32f5f176-d8e6-4f7c-a89c-1c1e55e06275
Spitzhorn, Lucas-Sebastian
9c868474-9ef0-40eb-91e8-ab85b34b2016
Silva, Maria Elena
6650a5d3-7e63-43f8-989b-afb3da84340e
Oreffo, Richard O.C.
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Hartung, Hans-Peter
70b96bb2-be18-4884-8c76-16c9b4b4cbdd
Prigione, Alessandro
eaa45004-0b06-406e-a45f-4ef59cbc077b
Rivera, Francisco J.
504cd10d-fdac-4361-bb48-fdef9bbf04c4
Adjaye, James
6b0559f7-9774-4496-b173-be530c90be0d
Kury, Patrick
99b0375b-1adb-4778-8f41-43a2c38b4120
Jadasz, Janusz J.
717deca1-4be6-4b99-bf6f-078158e612d2
Tepe, Lena
fca6279f-ccde-489d-becd-6fdfe5b0747a
Beyer, Felix
50711ff0-bd57-4b2f-a5e1-c34f3519b185
Samper Agrelo, Iria
8df23a3c-3c10-423b-817f-2ed5bbdeba89
Akkermann, Rainer
32f5f176-d8e6-4f7c-a89c-1c1e55e06275
Spitzhorn, Lucas-Sebastian
9c868474-9ef0-40eb-91e8-ab85b34b2016
Silva, Maria Elena
6650a5d3-7e63-43f8-989b-afb3da84340e
Oreffo, Richard O.C.
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Hartung, Hans-Peter
70b96bb2-be18-4884-8c76-16c9b4b4cbdd
Prigione, Alessandro
eaa45004-0b06-406e-a45f-4ef59cbc077b
Rivera, Francisco J.
504cd10d-fdac-4361-bb48-fdef9bbf04c4
Adjaye, James
6b0559f7-9774-4496-b173-be530c90be0d
Kury, Patrick
99b0375b-1adb-4778-8f41-43a2c38b4120

Jadasz, Janusz J., Tepe, Lena, Beyer, Felix, Samper Agrelo, Iria, Akkermann, Rainer, Spitzhorn, Lucas-Sebastian, Silva, Maria Elena, Oreffo, Richard O.C., Hartung, Hans-Peter, Prigione, Alessandro, Rivera, Francisco J., Adjaye, James and Kury, Patrick (2018) Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis. Glia, 66 (1), 145-160. (doi:10.1002/glia.23233).

Record type: Article

Abstract

The generation of new oligodendrocytes is essential for adult brain repair in diseases such as multiple sclerosis. We previously identified the multifunctional p57kip2 protein as a negative regulator of myelinating glial cell differentiation and as an intrinsic switch of glial fate decision in adult neural stem cells (aNSCs). In oligodendroglial precursor cells (OPCs), p57kip2 protein nuclear exclusion was recently found to be rate limiting for differentiation to proceed. Furthermore, stimulation with mesenchymal stem cell (MSC)-derived factors enhanced oligodendrogenesis by yet unknown mechanisms. To elucidate this instructive interaction, we investigated to what degree MSC secreted factors are species dependent, whether hippocampal aNSCs respond equally well to such stimuli, whether apart from oligodendroglial differentiation also tissue integration and axonal wrapping can be promoted and whether the oligodendrogenic effect involved subcellular translocation of p57kip2. We found that CC1 positive oligodendrocytes within the hilus express nuclear p57kip2 protein and that MSC dependent stimulation of cultured hippocampal aNSCs was not accompanied by nuclear p57kip2 exclusion as observed for parenchymal OPCs after spontaneous differentiation. Stimulation with human MSC factors was observed to equally promote rat stem cell oligodendrogenesis, axonal wrapping and tissue integration. As forced nuclear shuttling of p57kip2 led to decreased CNPase- but elevated GFAP expression levels, this indicates heterogenic oligodendroglial mechanisms occurring between OPCs and aNSCs. We also show for the first time that dominant pro-oligodendroglial factors derived from human fetal MSCs can instruct human induced pluripotent stem cell-derived NSCs to differentiate into O4 positive oligodendrocytes.

Text Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis_final (003) - Accepted Manuscript
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Accepted/In Press date: 29 August 2017
e-pub ahead of print date: 22 September 2017
Published date: January 2018

Identifiers

Local EPrints ID: 415145
URI: https://eprints.soton.ac.uk/id/eprint/415145
ISSN: 0894-1491
PURE UUID: 186c742d-ad56-4b3b-8740-41b7625ad91e
ORCID for Richard O.C. Oreffo: ORCID iD orcid.org/0000-0001-5995-6726

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Date deposited: 01 Nov 2017 17:30
Last modified: 03 Jan 2018 17:31

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Contributors

Author: Janusz J. Jadasz
Author: Lena Tepe
Author: Felix Beyer
Author: Iria Samper Agrelo
Author: Rainer Akkermann
Author: Lucas-Sebastian Spitzhorn
Author: Maria Elena Silva
Author: Hans-Peter Hartung
Author: Alessandro Prigione
Author: Francisco J. Rivera
Author: James Adjaye
Author: Patrick Kury

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