Mesenchymal Stem Cells Derived via Reprogramming of Old Cells Exhibit a Transcriptomic Signature Closer to that of Younger Cells and Pluripotent Cells

In today's open access paper and publicity materials, researchers report on an assessment of induced mesenchymal stem cells (iMSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were produced via the usual approach of reprogramming from tissue samples taken from old adults. The researchers then compared the gene expression profiles of these iMSCs with similar MSCs taken from fetal and adult tissues. They declare the the profile to be rejuvenated in comparison to that of the adult MSCs, but I think one has to be careful when using that word. We might better call the profile reflective of reprogramming, in that while it has commonalities with the fetal MSCs, it also has has commonalities with the iPSCs, expression of proteins usually not found in adult cells.

The reason for attempting this experiment is that there are concerns regarding the safety and efficacy of MSCs derived from the tissues of old individuals, such as in the case of autologous stem cell therapies. These cells are damaged and in some ways notably dysfunctional, such as in the decline of mitochondrial function. If those cells could be derived instead from a skin sample and then via iPSCs, with many of their age-related defects corrected along the way, acquiring a more beneficial phenotype, then perhaps this would be a better option. The question is always whether or not this is just unsafe in a different direction, such as risk of cancer. A great deal of work is going into answer that question.

Reprogramming somatic cells into iPSCs clearly repairs a range of age-related phenotypes exhibited by cells in old tissues, most notably mitochondrial dysfunction. Moreover, these cells begin to secrete signals that on balance beneficial for regeneration, inflammation, and other aspects of cellular metabolism that become problematic in aging. Most stem cell transplants provided in clinics today work in this way, producing benefits due to the signals issues by the transplanted cells, which soon die rather than integrating into tissues. This signaling and damage repair are the basis for experimental work in inducing pluripotency in the tissues of living animals, and for advances on that work such as the epigenetic not-quite-reprogramming of

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

The use of primary mesenchymal stem cells (MSCs) is fraught with ageing-related shortfalls such as limited expansion and early senescence. Human induced pluripotent stem cells (iPSCs) -derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these ageing-associated drawbacks. A collaborative study analysed the acquisition of rejuvenation-associated hallmarks in iMSCs. In their study, the team compared cellular features, transcriptomes and secretomes of iMSCs differentiated from embryonic stem cells (ESCs-H1) and iPSCs, emanating from MSCs isolated young and elderly individuals. The generated iMSCs (irrespective of source) met the criteria set out for MSCs and dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and distinct from pluripotent stem cells.

Irrespective of donor age and initial cell type, iMSCs acquired a rejuvenation-associated 50-gene comprising signature which is also expressed in pluripotent stem cells but not in the parental MSCs. Significantly, in terms of regenerative medicine, iMSCs acquired a secretome similar to that of primary MSCs, thus highlighting their ability to act via paracrine signalling. The iMSC concept has enabled circumventing the drawbacks associated with the use of adult MSCs and thus provide a promising tool for use in various clinical settings in the future.

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

Primary human bone marrow-derived stem cells (MSCs) contain a sub-population of multipotent stem cells. Due to highly proliferative, immune-modulatory properties, and paracrine orchestration, MSCs offer significant therapeutic potential for an increasing aging demographic. Although the bone marrow can be collected routinely to isolate MSCs, there are several drawbacks associated with the use of MSCs from aged individuals. 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. 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). 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. 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. Although the paracrine effects of iMSCs have been indicated, 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.