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Mesenchymal stem cells (MSCs) have been a topic of great interest in the last decade or so due to their ability to improve tissue regeneration merely by their presence and the secreted signals they give out.

Adult MSCs have traditionally been used for regenerative medicine with hit-and-miss results, depending on the quality and age of the harvested MSCs. It has been discovered in recent years that the efficacy of these cells greatly depends on how damaged by aging they are, which explains why MSC therapy sometimes works very well in one person but not so much in another.

However, what about aged cells that are reprogrammed back to pluripotency then guided into becoming mesenchymal stem cells through cellular reprogramming?

That was exactly what researchers wanted to find out in a new study, in which they assessed the gene expression profiles of induced mesenchymal stem cells (iMSCs). Following exposure to reprogramming factors, aged adult cells revert into induced pluripotent stem cells (iPSCs) and are then guided using additional factors into becoming the desired cell type, in this case, iMSCs. The researchers set out to see if there is a significant difference in gene expression between regular aged MSCs, fetal MSCs, and reprogrammed iMSCs.

As part of reprogramming, the iMSCs acquired a gene expression signature that is associated with rejuvenation and is only normally seen in pluripotent stem cells but not in adult MSCs; importantly, this was irrespective of the donor age of the original adult cells or their type. Also, the iMSCs secreted similar signals to those seen in adult MSCs.

The result of their investigation suggests that iMSCs are rejuvenated compared to regular aged MSCs; in other words, their gene expression profile is significantly different from old cells and closer to those of young cells.

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.

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.

Conclusion

The use of iMSCs has great potential in circumventing the issues inherent in using aged MSCs. One potential solution is to harvest adult cells from skin samples, reprogram them back into iPSCs, and turn them into iMSCs while erasing various cellular aging markers in the process.

Clearly, some level of rejuvenation is occurring in these reprogrammed cells, and it is yet more evidence for the potential of full and partial cellular reprogramming. There is now considerable interest in cellular reprogramming, with a number of companies working towards the practical application of these techniques in humans in order to engineer tissue and combat age-related diseases. We are optimistic that this could dramatically change the face of medicine in the next decade or so.

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Literature

[1] Spitzhorn, L. S., Megges, M., Wruck, W., Rahman, M. S., Otte, J., Degistirici, Ö., … & Adjaye, J. (2019). Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature. Stem cell research & therapy, 10(1), 100.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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