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.


As I've mentioned previously, reprogramming is the area which excites me the most after snolytics. I think this field is going to explode in the next few years, as evinced by the following new podcast with David Sinclair, where he provides new details about reprogramming work undertaken in his lab in the last year (amongst other topics):

Posted by: Chris Linnell at April 22nd, 2019 5:58 PM

Reprogramming itself call be done more or less easily, after so many years of research. The problem is to instigate the right growth and differentiating process. We want to induce pluripotency but avoid tumors and malformations.

So in a way the first generation stem cells treatments failed to differentiate the implanted stem cells but that was a good thing since they were safe. I remember if one case a few years ago where a woman got injection in her eyelids and mini bones started to form. Apparently, that treatment protocol managed to preserve the stem cells, so they didn't die but started differentiating and forming tissues. Unfortunately, wrong toe of tissues in the wrong place...

Posted by: Cuberat at April 22nd, 2019 8:15 PM

Hi Cuberat - yes, I agree with you. I should have been more specific when mentioning reprogramming. I meant transient or partial reprogramming, which rejuvenates the cell/organism whilst avoiding the formation of teratomas or other cancerous formations.

Posted by: Chris Linnell at April 23rd, 2019 12:14 AM

Today, the idea of using Conditioned Medium from Human Mesenchymal Stromal Cells is encouraging, but unlike the authors of this article (, the Mesenchymal Stromal Cells must be previously irradiated as in the article ( to activate the alarm signaling for regeneration. Also a source of controlled prolonged release of ROCK inhibitor [] must be added. Vector of Δ133p53α (a natural p53 isoform), which induces hTERT expression and telomerase activity [], can be used instead of irradiated cells. See more details in

Posted by: Dzhagarov at April 23rd, 2019 3:02 AM

As Reason repeatedly points out, it is the signalling of these induced stem cells that is critical, and this also lays behind the cancer risk. So long as the signalling is not too strong, which means the number of cells is not too high, no terratomas will form. Therefore iPSCs can be injected into circulation and form no terratomas. Plus because these cells are small and can cross various tissue barriers without impediment, they can locate to a site of injury and differentiate, effecting repairs (unlike adult stem cells, which are useful for repair in far more limited scenarios). The evidence for what I am saying is here:

Reason implies that the cancer risk comes from the fact some cells are still 'damaged' in an obscure way that has not been fixed by epigenetic reprogramming. However, as I explain above, the cancer risk comes when the reprogrammed cells override the signalling of the tissue in which they are placed, not from 'damage'.

Either injecting iPSCs or as Dzhagarov points out, a conditional reprogramming approach, is going to revolutionise health care and will form one of the main planks of a rejuvenation therapy in the next 20 years.

Posted by: Mark at April 23rd, 2019 5:25 AM

teratoma risk is also heavily dependent on the exposure to reprogramming factors, you want a partial reprogram enough to erase the aging markers but not enough to loose cell identity. This is ~4 days in many tissue types but it depends on the target cell. It is perfectly plausible and already demonstrated to be able to separate the aging marker reset portion from the cell memory portion of the process as the markers are reset earlier in the process. Partial reprogramming has a huge amount of potential given that epigenetic alterations are a primary cause of aging.

Posted by: Steve Hill at April 23rd, 2019 6:01 AM

Teratoma formation is a morphodynamics issue

This has been known since the 1970's and the seminal work by Dr. Beatrice Mintz et. al in Philadelphia ( in embryos

Rejuvenation with any of these cell types must take into account the morphodynamic processes occurring in the ADULT human body

The organisms on this planet that have the ability to reliably turn back "biologic age" in some (or all) of their bodies, using some form of reprogramming, possess two important inherent attributes. These are:

1) The ability to re-establish the "embryogenic" potential of their cells / genomes,


2) The simultaneous ability to re-establish the "morpho-dynamic" architecture of their tissues / organs / limbs / body segments, once such embryogenic potential is re-established.

The last 100 years of regenerative biology research has shown that one, without the other, is an incomplete path towards rejuvenation.

Posted by: Ira S. Pastor at April 23rd, 2019 6:25 AM

@ Steve - everyone is focussing on partial reprogramming because we supposedly want to maintain somatic cell identity. But what I'm saying is that this may not be necessary. An IV drip of iPSCs may be preferable. Somatic signalling will dominate the (relatively small number of) added cells and they will differentiate appropriately, satisfying the "architecture of tissues" as Ira says, rather than inappropriately, as with terratomas.

This is analogous to the in vivo work on age accelerated mice, where they induced reprogramming for a limited time, rather than on a limited number of (ex vivo) cells. Obviously in vivo is higher risk. Given ex vivo will be affordable (everyone in the cancer immunotherapy space is working on it), it seems the more pragmatic option.

Posted by: Mark at April 23rd, 2019 10:22 AM

We will see. I am optimistic we can have our cake and eat it, it's all about exposure time.

Posted by: Steve Hill at April 24th, 2019 3:35 AM

Hi Ira! Just a 2 cents.

Do you think that epireprogrammed cells (via yamanaka) have this possibility of remorpho-dynamically remaking architecture of tissues and organs, but in very aged adult body/like an elder of 90+ years old, specifically ?

When I look at the litterature, it says that by this age, the damage accumulated is just 'highly consequential' (or too consequential?) to be able 'to revert' to young 'architecture' of tissues/organs..
meaning, it has come to stocastich 'irreversibility' of current architecture, because it's so late (90 years later), the person's body is just not 'reversible enough' aymore....just like a epigenome that cannot bounce back by itself (if it using no epireprogramming but 'regular epiaging').

That worries me because it would mean (just guessing) that there is a irreversibility point to epiprogramming - that the epigage of cell can be reversed zero but it does not mean Reversal of Architecture of tissues/organs, neither. For that to happen, the environment - still young enough - must be so to 'allow that possibilty', as you said, like a eternal hydra jellyfish which has telomerase germ cell line in its tissue and can revert its 'adult/mature' state to a immature child state (by its own self-epiReprogramming program after sexual reproduction).

Thus, there could be a 'cut off/tipping' point/'PONR (point of no return)'..if you past this age, the likeliness of reversal of organs/tissues to morphogenic architecture is not feasible anymore because of so many 'changes'/epialterations accumulated at late age and in the architecture. The damages, so late, may then be too consequential to allow rearchitecturing.

It's oftently what happens with very advanced diseases, it seems like irreversible; I want to believe that is reversible, and I hope it is. When I look at hydras jellyfish they do it...but do not go to point PONR...they don't age so Late that it's 'TOO late' for it...

and this whole epigenetic reprogramming is confirming that - you have a 'window' or 'it's too late' get cancer/Teratoma formation...I'm starting to think that, in a very aged body, it'S the same thing - too late/irreversible. I hope I'm wrong though, in the litterature, there is basically 0 animal that can reach imm*rtal state by epireprogramming - at a Very Late age/old state...the trick is they keep 'old enough/young enough' to make it still viable/feasible/possible. Too late/Too too late/too old. Let's keep fingers crossed and hope that we can Overcome the 'cumul' curve of aging and rearchitecture them to a young may take long, but does not long as it make it happen and Reverse an very old body to a young body. But, not holding breath. Rejuvenation/age reversal was, it seems, something is a 'time limit' to it and can't wait 'forever' to do it (there is such a thing a too late).

Just a 2 cents.

Posted by: CANanonymity at April 24th, 2019 10:03 AM

PS: I see two possible main outcomes of this

1- In very late aged (above 90) = therapeutic/health promoting, the person may get a extra few years (10 or so), but they will die around 120 MLSP. This will make healthy aging, not reversal of aging.

2- In younger age (below 60) = longevity creating, it could very possibly make humans go above MLSP and then, the possibility of LEV would be concrete and not so remote anymore, the trick is making that epireprogramming continuously back to epiage of 0, but staying in that 'no later than 60 or so' in current architecture of organs/tissues - to continuously allow repeated reprogramming (that is something not spoken oftenyl Repeatability of Reprogramming - Re - Re RE......forever in loop di loop, how many times can we do it until death happens, if we reverse, it could be eternally, but nothing says that that is a possbility if we cannot keep organ architecture intact to that of someone young enough, to still that possibility or 'repetaed' reverser re-re-re-..reepireprogramming and Re-re-re-...rearchitecturing). I await that studies do it ****Repeateadly**, not once and 'called it a day', that's mostly not very 'telling'/just surface it Repeated/continuously/on and on, and then will see how viable this is over multiple repeated times (like will we get teratoma formation/cancer?/it is still architecturally 'sound'), over a long time; this would confirm us the True repeatability of it and, if so, LEV would thus Then be truly possible.

Posted by: CANanonymity at April 24th, 2019 10:44 AM

@CANanonymity - at least on a cellular level there doesn't appear to be a point of no return. I remember a few years back, they took cells from people of different ages, including centenarians, and reverted them back to the pluripotent state (iPSCs). They found that there was no discernable difference between someone in their twenties and someone over a hundred. What this means for an entire organ or organism remains to be determined.

By the way, there was yet another podcast with David Sinclair released yesterday, which is longer & better than the one I posted above. After the hour and a half mark, he talks in detail about this and the future possibilities which might emerge - well worth a listen:

Posted by: Chris Linnell at April 24th, 2019 12:12 PM

Hi Chris! Thanks for that..I did some more digging and foudn this...I think this could answer my question, partially and thus gives up much hope.

''Two key insights came when fibroblasts from LAKI progeria mice were analyzed after OSKM expression was terminated. First, it was shown that the age-associated phenotypes return but, strikingly, ****they could be reversed again if OSKM expression was reintroduced****: cyclic expression of OSKM maintained the reversal of age-associated phenotypes''

This would support the repeatability of things and epireprogramming, as something that continuously be repeated/looped forever for it erases (the epimethylation code on DNA) all traces of 'tabs' on aging/by reverting epiclock/epiage.

''...The cyclical regime for OSKM expression was then used in vivo, with expression for 2 days and no expression for 5 days. This cycle could be repeated as often as required. Cyclic expression of OSKM in LAKI mice had a dramatic effect. Not only were age-associated features reversed but there was also a significant increase in both median and ***maximal life span***''

''There was no increase in formation of teratomas or mortality in vivo. "Partial reprogramming" did not lead to the loss of differentiation markers and expression of pluripotency markers such as Nanog, indicating that age reprogramming in vivo can be achieved in the absence of developmental reprogramming''

''On the other hand, doxycycline treatment in LAKI mice not carrying the 4F cassette did not lead to any improvement in the lifespan compared to untreated controls (Figure 4B). Significant improvements in external appearance, including a reduction in spine curvature, were observed in LAKI 4F mice subjected to cyclic OSKM induction (Figures 4C and S4A). Detailed necropsy analyses performed at 14 weeks of age after 6 weeks of cyclic induction of OSKM revealed gross improvement in the appearance of the gastrointestinal tract in doxycycline-treated LAKI 4F mice compared to untreated mice (Figure 4D). Age-associated histological changes are normally observed during physiological aging in multiple organs, including the skin, spleen, kidneys, and stomach (Cesta, 2006; Khanna et al., 1988; Kurban and Bhawan, 1990; Zhou et al., 2008). Importantly, many of these histological changes were improved in 14-week-old LAKI 4F mice subjected to cyclic induction of OSKM during 6 weeks compared to untreated mice (Figure 4E). Doxycycline-treated LAKI 4F mice showed an increased epidermal and dermal thickness and decreased keratinization of the skin compared to untreated controls (Figure 4E). Macroscopic involution of the spleen and lymphoid depletion of the white pulp, visualized by the reduced size of germinal centers, was significantly rescued in LAKI 4F mice after cyclic induction of OSKM (Figures 4E and S4B). Moreover, we observed a decrease in tubular atrophy and interstitial volume in kidneys of doxycycline-treated LAKI 4F mice compared to untreated mice (Figure 4E). Lastly, age-associated loss of parietal cells and thinning of gastric epithelium in the stomach were also rescued by cyclic induction of OSKM''

Clearly, this means morpho-architecture restoring, or least, partial restoring because of the age-related changes seem reversed by OSKM; the ECM is Definitely affected by OSKM (the likes of MMP/matrix metalloproteinase are affected by OSKM), that is a major effect. This would mean that there the morpho dynamic of multiple tissues/organs - Can Be Reversed to that of a younger age (again, at least, is, Partial Reprogramming, after all, in order to avoid teratoma formation after 11 days of OSKM exposure).

What worries me much more is the fact that OSKM was not enough to make complete abolition of progeria effect in LAKI mouse, so this still succombed of progeria even so - just a bit later instead (like 10 weeks later/a bit less than 3 months later, which in mouse lifespan translates as 10-15% increase of lifespan; in progeric mice at least).

The riddle is what happens in healthy mice, and if OSKM regimen started at birth.

''As was seen with mouse WT 4F TTFs, short-term OSKM induction in human 4F cells significantly reduced the number of foci of histone γ-H2AX per cell compared to untreated cells (Figure 6E). In addition, short-term induction of OSKM in human 4F cells significantly restored the levels of H3K9me3 (Figure 6F).

Collectively, these results suggest that short-term induction of OSKM can ameliorate multiple hallmarks of aging in late-passage WT mouse and human cells, including the accumulation of DNA damage, cellular senescence, and epigenetic dysregulation, thus demonstrating the potential of partial reprogramming for the rejuvenation of phenotypes observed during physiological aging.''

'' Interestingly, the number, intensity, and volume of foci for histone γ-H2AX, a marker of nuclear DNA double-strand breaks associated with aging (López-Otín et al., 2013), were significantly reduced by short-term induction of OSKM in LAKI 4F cells compared to untreated cells (Figures 1B and S1D). Similarly, levels of p53 binding protein 1 (53BP1), which participates in the DNA damage response, were reduced as a consequence of short-term induction of OSKM (Figure S1E). Furthermore, short-term induction of OSKM in LAKI 4F cells downregulated the expression of age-related stress response genes in the p53 tumor suppressor pathway, including p16INK4a, p21CIP1, Atf3, and Gadd45B, as well as the senescence-associated metalloprotease MMP13 and interleukin-6 (Figure 1C). Additionally, senescence-associated β-galactosidase activity was reduced in LAKI 4F cells by short-term induction of OSKM''

At least thagt is good news, and it seems that organ/tissue reversal is possible, even from very aged people. The fact that senescence is Greatly reduced is a demonstration that it affects all type of senescence, including the most important one, Replicative Senescence/Hayflick, possibly in post-mitotic somatic long-lived non-dividing cells. This means, OSKM, is not just partial rejuvenation, it is True rejuvenation, if not 100% (From telomeres elongation, ECM changes reversal, reduction mtROS, reversal of DNA epiclock age, reduction of DNA frags, I would wager reduction of progerin (seen in progeric mice) and also proteasome/lysosome lipofuscin; maybe it is sufficient (even if partial) and repeatable to actually reverse aging in True rejuvenation, no matter if 90 or 60 years old.

Still, until they make the WT mice obtain OSKM and see how much it extends their natural healthy lifespan, the question lingers. Progeria mice do not escape their progeric condition despite OSKM.
My take:
It will depend if OSKM is started, at BIRTH or OLD age of WT mice, and then we will see how much OSKM is really extending longevity in WT mice depending on When it was started in the mouse's lifespan.

1. Age reprogramming and epigenetic rejuvenation

2. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity

3. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

Posted by: CANanonymity at April 24th, 2019 4:19 PM

Imagine the market size if partial reprogramming of people's skin cells made their skin look younger?

Posted by: jimofoz at April 25th, 2019 4:35 AM

Hi #CANanonymity

You always go through an excellent thinking process in your posts

The history of somatic cell reprogramming, going back to the Briggs and King experiments from 1952, highlights the potency of all of these processes in turning back cellular age / identity -

The big mystery is how you deal with with all that was learned in the ensuing "cross-age transplantation" era (1950s-1980s) - which showed that putting "young things" into "old organisms" was not a very good long term strategy towards rejuvenating an organism -

Some good chapters in this book on the history of that work -

That is the true "black box" of longevity biotech that must be solved

As mentioned above, regenerative organisms wield the simultaneous ability to re-establish the morphodynamic developmental processes, along side embryogenic cellular potential

Posted by: Ira S. Pastor at April 25th, 2019 6:07 AM

Re - Thanks for that Ira (and you too do an excellent thinking process), and the links, will check that.
Just a 2 cents. I think we are now at that point, matured enough, that we feel much more confident on the realization/potential and scalability of the rejuvenation from reprogramming; it took a long time (1952 to now (nearly 70 years...but, finally, we arrived). In fact, it's those kind of old papers that put marvel/awe in me - and - also, disbelief at the same time (the more 'less awe/amazed', thus the bit 'depressed' kind of disbelief) wow it takes, time, (lotsa) for things to happen (we are patient, but impatience always comes at one point of late, then its depression as how hope fades)...but 70 years is done, and now we are now. So we are eternally grateful to these pioneers of old times for making these small stepping milestones, setting it in place/for it to happen today, some seven decades later. The more I read of science the more it's 'all over the place' a miracle Could happen LEV...let's say...or we could be 'searching for needles in haystacks'...for Another Next 7 decades...that's what it is (who has seven decades?). It also means that we must be 'take it one day at a time' and be optimistic yet realist on things changing in the near-future (near-future, like say, less than 30 years; thus who wants to wait another seven decades). Because of the uncertainty/unassurance/unguarantee of things (biogerontology is a 'odds thing/gamble'/nebulous ambiguous contradictory results 'at odds with self', every day is a gene roulette spin), we must keep realist and hope for best (and prepare for worse too, Should it happen, something we hope not). But, for people that are very sick (right now), it'S even more imperative, they follow this like lazer-beam precision, because time is missing for them.

I think OSKM is our first step in the true biorejuvenation domain; it is spectacular, and I wager, it will only get better as we hone it. LEV then becomes far more a concrete possibility; maybe not LEV, exactly, but if humans obtain 150-300 years extra in life above their max - that will, already, be the most incredible achievement Ever; we are inching closer and closer to curing diseases, aging and death.
I hope to be alive in next few decades to see that happen. Just a 2 cents.


Hi jimofoz! Just a 2 cents. Indeed, it would be Incredible/Giganormous for sure. When I look at things like antioxidants, supplements, collagen peptides, collagen injection, botox injection, retinoic acid for skin, it is a big market for sure...but I think it will take more than that. We have to convey it's more than just 'skin reversal' of is Whole Systemic reversal of aging - pushing death as far as possible..that's a lot more meaningful than looking young in the face only. People must understand taht All Organs/cells benefit, thus this affects Entire Aging. This will make them understand the power of this and think ''I can get beautiful young when I was 20...long ago...but more than that, I can live Long(er), much longer and (maintain) in great health - I feel renewed sense of purpose/desire to live a life, my life, and it will last much longer. I have lots of time ahead now and can do whatever I please for my life will last long''. Kind of like the 'energizer bunny' (battery ad) will keep on going..and going..and going....Who wants a 1.5 Volt battery..we all want a 9 Volt - 9 lives Cat Rayovac battery (imagine having '9 lives like a cat').

Just a 2 cats.

Posted by: CANanonymity at April 25th, 2019 1:52 PM

My goodness @CANanonymity, I've never seen you this positive before! It's nice to see :-)

Posted by: Chris Linnell at April 25th, 2019 2:24 PM

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