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

aged msc fetal mscs ipscs imscs transcriptome secretome rejuvenation aging

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#1 Engadin

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Posted 30 April 2019 - 04:08 PM


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 INHBEDNMT3BPOU5F1P1CDKN1C, 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 (COX7AEZA2, and TMEM119) and aging (CXADRand 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.

 

 

BACKGROUND

Primary human bone marrow-derived stem cells (MSCs) contain a sub-population of multipotent stem cells which retain osteogenic, chondrogenic, and adipogenic differentiation potential [12]. Apart from the adult sources, these multipotent MSCs have been isolated from fetal femur [3]. Due to highly proliferative, immune-modulatory properties, and paracrine orchestration, MSCs offer significant therapeutic potential for an increasing aging demographic [4].

 

Although the bone marrow can be collected routinely to isolate MSCs, there are several drawbacks associated with the use of MSCs from aged individuals. Aging involves enhanced cellular senescence, instability of the genome, accumulation of DNA damage, changes in DNA repair pathways, oxidative stress, metabolic instability, and activated immune response [5678]. In line with this, the expansion possibilities and application potential of primary MSCs are limited, in part, by changes in the differentiation/response potential and function of MSCs isolated from aged donors [91011]. However, to date, it remains unclear whether there are any age-related differences in transcriptome and secretome signatures between human fetal MSCs and MSCs from elderly donors.

 

Recent studies have shown that the shortfalls associated with primary MSCs can be circumvented by reprogramming them to induced pluripotent stem cells (iPSCs) [121314]. iPSCs have the potential to self-renew, bypass senescence and are similar to human embryonic stem cells (ESCs). However, the parental somatic aging signature and secretome properties and subsequent reflection in iPSC derivatives are unknown [151617]. An iPSC-derived cell type that is of prime interest for circumventing shortfalls associated with primary MSCs are MSCs differentiated from iPSCs and ESCs (iMSCs). The similarity of iMSCs to primary MSCs and their regenerative potential in vivo has already been demonstrated [1819]. Moreover, the reflection of donor age in iMSCs was shown to be reverted into a younger state and at the same time reflected in iMSCs from patients with early onset aging syndromes [1320]. Although the paracrine effects of iMSCs have been indicated [21], relatively little is known about the potential to rejuvenate the paracrine features of MSCs from elderly patients via iMSC generation.

 

 

In view of this, there is a dire need to clarify in more detail whether age-related features inherent to primary MSCs isolated from elderly patients are retained in the corresponding iMSCs at the transcriptional, secretome, and functional level. In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60–74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of their parental MSCs, thus re-enforcing their capabilities of context-dependent paracrine signaling relevant for tissue regeneration.

 

 

Rest at source: https://stemcellres....3287-019-1209-x

 







Also tagged with one or more of these keywords: aged msc, fetal mscs, ipscs, imscs, transcriptome, secretome, rejuvenation, aging

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