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Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature

Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature
Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature

Background: Primary mesenchymal stem cells (MSCs) are fraught with aging-related shortfalls. Human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these aging-associated drawbacks. To date, the extent of the retention of aging-hallmarks in iMSCs differentiated from iPSCs derived from elderly donors remains unclear. Methods: Fetal femur-derived MSCs (fMSCs) and adult bone marrow MSCs (aMSCs) were isolated, corresponding iPSCs were generated, and iMSCs were differentiated from fMSC-iPSCs, from aMSC-iPSCs, and from human embryonic stem cells (ESCs) H1. In addition, typical MSC characterization such as cell surface marker expression, differentiation capacity, secretome profile, and trancriptome analysis were conducted for the three distinct iMSC preparations - fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs. To verify these results, previously published data sets were used, and also, additional aMSCs and iMSCs were analyzed. Results: fMSCs and aMSCs both express the typical MSC cell surface markers and can be differentiated into osteogenic, adipogenic, and chondrogenic lineages in vitro. However, the transcriptome analysis revealed overlapping and distinct gene expression patterns and showed that fMSCs express more genes in common with ESCs than with aMSCs. fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs met the criteria set out for MSCs. Dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and separated from the MSC-iPSCs and ESCs. iMSCs irrespective of donor age and cell type acquired a rejuvenation-associated gene signature, specifically, the expression of INHBE, DNMT3B, POU5F1P1, CDKN1C, and GCNT2 which are also expressed in pluripotent stem cells (iPSCs and ESC) but not in the parental aMSCs. iMSCs expressed more genes in common with fMSCs than with aMSCs. Independent real-time PCR comparing aMSCs, fMSCs, and iMSCs confirmed the differential expression of the rejuvenation (COX7A, EZA2, and TMEM119) and aging (CXADR and IGSF3) signatures. Importantly, in terms of regenerative medicine, iMSCs acquired a secretome (e.g., angiogenin, DKK-1, IL-8, PDGF-AA, osteopontin, SERPINE1, and VEGF) similar to that of fMSCs and aMSCs, thus highlighting their ability to act via paracrine signaling. Conclusions: iMSCs irrespective of donor age and cell source acquire a rejuvenation gene signature. The iMSC concept could allow circumventing the drawbacks associated with the use of adult MSCs und thus provide a promising tool for use in various clinical settings in the future.

Aged MSC, Aging, Fetal MSCs, iMSCs, iPSCs, Rejuvenation, Secretome, Transcriptome
1757-6512
Spitzhorn, Lucas Sebastian
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Megges, Matthias
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Wruck, Wasco
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Rahman, Md Shaifur
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Otte, Jörg
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Degistirici, Özer
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Meisel, Roland
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Sorg, Rüdiger Volker
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Oreffo, Richard O.C.
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Adjaye, James
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Spitzhorn, Lucas Sebastian
9c868474-9ef0-40eb-91e8-ab85b34b2016
Megges, Matthias
cfd85846-b8ae-4239-87f3-113d4eca44f2
Wruck, Wasco
cbff1ea0-b3e9-4868-8b4c-4fbe655a9a15
Rahman, Md Shaifur
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Otte, Jörg
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Degistirici, Özer
8dcd5e3d-f27d-4a5e-a0d6-10a995a7d3db
Meisel, Roland
fdb82e9d-141f-4787-882b-f1f4cb80098d
Sorg, Rüdiger Volker
063ee8dc-e394-4cbc-9f36-d0a15a72d7e6
Oreffo, Richard O.C.
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Adjaye, James
6b0559f7-9774-4496-b173-be530c90be0d

Spitzhorn, Lucas Sebastian, Megges, Matthias, Wruck, Wasco, Rahman, Md Shaifur, Otte, Jörg, Degistirici, Özer, Meisel, Roland, Sorg, Rüdiger Volker, Oreffo, Richard O.C. and Adjaye, James (2019) Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature. Stem Cell Research and Therapy, 10 (1), [100]. (doi:10.1186/s13287-019-1209-x).

Record type: Article

Abstract

Background: Primary mesenchymal stem cells (MSCs) are fraught with aging-related shortfalls. Human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these aging-associated drawbacks. To date, the extent of the retention of aging-hallmarks in iMSCs differentiated from iPSCs derived from elderly donors remains unclear. Methods: Fetal femur-derived MSCs (fMSCs) and adult bone marrow MSCs (aMSCs) were isolated, corresponding iPSCs were generated, and iMSCs were differentiated from fMSC-iPSCs, from aMSC-iPSCs, and from human embryonic stem cells (ESCs) H1. In addition, typical MSC characterization such as cell surface marker expression, differentiation capacity, secretome profile, and trancriptome analysis were conducted for the three distinct iMSC preparations - fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs. To verify these results, previously published data sets were used, and also, additional aMSCs and iMSCs were analyzed. Results: fMSCs and aMSCs both express the typical MSC cell surface markers and can be differentiated into osteogenic, adipogenic, and chondrogenic lineages in vitro. However, the transcriptome analysis revealed overlapping and distinct gene expression patterns and showed that fMSCs express more genes in common with ESCs than with aMSCs. fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs met the criteria set out for MSCs. Dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and separated from the MSC-iPSCs and ESCs. iMSCs irrespective of donor age and cell type acquired a rejuvenation-associated gene signature, specifically, the expression of INHBE, DNMT3B, POU5F1P1, CDKN1C, and GCNT2 which are also expressed in pluripotent stem cells (iPSCs and ESC) but not in the parental aMSCs. iMSCs expressed more genes in common with fMSCs than with aMSCs. Independent real-time PCR comparing aMSCs, fMSCs, and iMSCs confirmed the differential expression of the rejuvenation (COX7A, EZA2, and TMEM119) and aging (CXADR and IGSF3) signatures. Importantly, in terms of regenerative medicine, iMSCs acquired a secretome (e.g., angiogenin, DKK-1, IL-8, PDGF-AA, osteopontin, SERPINE1, and VEGF) similar to that of fMSCs and aMSCs, thus highlighting their ability to act via paracrine signaling. Conclusions: iMSCs irrespective of donor age and cell source acquire a rejuvenation gene signature. The iMSC concept could allow circumventing the drawbacks associated with the use of adult MSCs und thus provide a promising tool for use in various clinical settings in the future.

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Accepted/In Press date: 6 March 2019
Published date: 18 March 2019
Keywords: Aged MSC, Aging, Fetal MSCs, iMSCs, iPSCs, Rejuvenation, Secretome, Transcriptome

Identifiers

Local EPrints ID: 430069
URI: http://eprints.soton.ac.uk/id/eprint/430069
ISSN: 1757-6512
PURE UUID: 8741c904-7888-4cc5-8900-c609b171a9ef
ORCID for Richard O.C. Oreffo: ORCID iD orcid.org/0000-0001-5995-6726

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Date deposited: 11 Apr 2019 16:30
Last modified: 07 Oct 2020 01:44

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Contributors

Author: Lucas Sebastian Spitzhorn
Author: Matthias Megges
Author: Wasco Wruck
Author: Md Shaifur Rahman
Author: Jörg Otte
Author: Özer Degistirici
Author: Roland Meisel
Author: Rüdiger Volker Sorg
Author: James Adjaye

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