Progress Towards Ways to Make Old Stem Cells More Effective for Heart Repair

Stem cells in old tissues are less active than stem cells in young tissues, meaning a lesser supply of cells to maintain the tissue, and a consequent slow loss of function. The evidence to date suggest that a sizable part of this decline is a reaction to rising levels of tissue damage and the changing balance of cell signaling that results from that damage. There is certainly damage occurring to stem cells themselves, but that doesn't appear to contribute to as great a degree until very late in life. This means that it is feasible to think about ways to force stem cells to get back to work, to rejuvenate their behavior if not their level of intrinsic damage, and assess the benefits against the potential risks, such as a higher rate of cancer. The stem cell therapies of the past few decades suggest that this cancer risk is lower than was expected, that evolution has left us more wiggle room for therapeutic enhancement of stem cell activity in the old than it might have done.

Ischemic heart disease affects a majority of people, especially elderly patients. Recent studies have utilized autologous adult stem cells and progenitor cells as a treatment option to heal cardiac tissue after myocardial infarction. However, donor cells from aging patients are more likely to be in a senescent stage. Rejuvenation is required to reverse the damage levied by aging and promote a youthful phenotype. This review aims to discuss current strategies that are effective in rejuvenating aging cardiac stem cells and represent novel therapeutic methods to treat the aging heart.

Recent literature mainly focuses on three approaches that aim to reverse cardiac aging: genetic modification, pharmaceutical administration, and optimization of extracellular factors. In vitro genetic modification can be used to overexpress or knock down certain genes and allow for reversal of the aging phenotype. Pharmaceutical administration is another approach that allows for manipulation of signaling pathways related to cell proliferation and cell senescence. Since the stem cell niche can contribute to the age-related decline in stem cell function, rejuvenation strategies also include optimization of extracellular factors.

Overall, improving the intrinsic properties of aging stem cells as well as the surrounding environment allows these cells to adopt a phenotype similar to their younger counterparts. Recent studies show promising results of the ability of these techniques to rejuvenate the aging heart. However, more understanding of the combinatorial effects of these interventions and fine-tuning of these techniques is required to evaluate the translational potential of these methods. Each strategy has its own advantages and disadvantages. The success of myocardial regenerative treatment will require teamwork across various disciplines to make stem cell therapy a reliable method for cardiac repair.



Wouldn't it be great if manipulating stem cells and immune cells (as state machines) represented the end game for SENS?

Posted by: Tom Schaefer at May 25th, 2018 12:26 PM

For some reason I have read the tile as "hair repair" . How hard would it be to grow hair follicle from induced pluripotent stem cells? Seems like low risk not very invasive therapy.

I guess if we can revert the stem cells to utheful state, probably do some genetic enhancements , culture then and deliver to the heart out any other organ then we could solve the stem cell depletion problem.

Mobilizing the pre-existing cells using signals and factors is exciting but I am afraid it can bring you only that far...

Posted by: Cuberat at May 25th, 2018 7:44 PM

Yes, that might be an easier (or more controllable) way to do gene therapy generally - especially if you wanted to alter or insert several genes (as in the mitoSENS allotopic expression thing). So it could be used for more than addressing stem cell depletion.

This approach might not work if the stem cell niche causes the transplanted stem cells to change to the aged epigenetic state; Hovarth states here that in the case of transplanted hematopoetic stem cells, that doesn't happen:

Posted by: CD at May 26th, 2018 11:00 AM

I wonder why no one has done the following experiment (btw I'm not a medical professional):

Take a middle aged mouse (say 12 months old), make a younger clone of it (say 3 months old), and attach the younger clone in parabiosis. Now the younger clone should supply the older mouse with young stem cells that are genetically identical.

After 3 months remove the younger clone (which is now 6 months old), and attach a new younger clone (say 3 months old again) to the 15 months old mouse.

Repeat the procedure every 3 months with a fresh young clone until the old mouse dies.

I wonder wouldn't such an experiment provide plenty of insights of the role of stem cells in rejuvenating the body as it ages?

Posted by: Sanchez at May 26th, 2018 7:09 PM

Parabiosis don't transport stem cells.

Posted by: Antonio at May 27th, 2018 1:45 AM

It is very important to rejuvenate the heart muscle considering that the death from heart failure is the number one killer
I would add to this article recent successful attempts (in the experiments on mice) to resist postinfarction fibrosis - the degeneration of the heart muscle into the connective tissue - by chemical in vivo reprogramming of cardiac fibroblasts into cardiomyocytes. with a cocktail CRFVPTM (C, CHIR99021; R, RepSox; F, Forskolin; V, VPA; P, Parnate; T, TTNPB; M, Rolipram).
Drug treatment
CRFTM, including CHIR99021 (C, 14 mg/kg), Repsox (R, 8.6 mg/kg), Forskolin (F, 61.6 mg/kg), TTNPB (T, 1 mg/kg) and Rolipram (M, 2.5 mg/kg), were mixed in 0.5% CMC-Na (sodium carboxymethyl cellulose)/saline. VP, including VPA (V, 250 mg/kg) and Parnate (P, 2.7 mg/kg), were dissolved in saline. Mice were treated with C6FTR by oral gavage and VP by intraperitoneal injection. Mice were given CRFVPTM once a week for 6 weeks. And this combination reduce the formation of fibrotic tissues after myocardial infarction.

Posted by: Dmitry Dzhagarov at May 28th, 2018 10:15 AM

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