FightAging!
3-31-19
https://www.fightaging.org/archives/2019/03/on-adult-cardiac-stem-cells-and-their-aging/
Does the adult mammalian heart contain a population of stem cells capable of tissue repair? If so, they are not very active; the heart is one of the least regenerative of organs, alongside the brain and the rest of the central nervous system. Opinions and study results differ on whether or not cardiac stem cells exist in any meaningful sense in the adult heart. If they do, there is the possibility of coercing them into greater efforts in tissue maintenance. This is possibly a faster path to regeneration of a damaged or aging heart than any of the other options. However, this would also require that these stem cells not only exist, but also survive into old age in a sizable enough population to produce regeneration. This is another area of study in which there are more questions than answers.
Until the new millennium, the adult heart was considered a postmitotic organ, but several recent studies have supported the notion that it possesses a population of endogenous cardiac stem/progenitor cells (CSCs) supporting myocardial cell turnover and regeneration due to their intrinsic potential to differentiate in all cardiac cell lineages. This discovery opened a new era for myocardial regeneration where endogenous cardiac stem/progenitor cells were introduced as direct regenerative agents and/or endogenous targets of regenerative therapy to effectively replenish the heart muscle cells, lost by injury and/or age, in order to improve/normalize myocardial function.
However, the pathological and pathophysiological cardiomyopathy that occurs with age also affects the stem cell microenvironment modifying adult stem cell biology and then their ability, during lifespan, to repair damaged tissues and organs. Accordingly, as shown for other stem cell types, cardiac stem cell (CSC) potential has also been found to be compromised or even lost with aging as a consequence of the accumulation and activation of senescence factors affecting myocardial homeostasis, producing DNA damage, and alteration of the telomere-telomerase system eventually leading to a senescent phenotype of CSCs. Despite this evidence, interesting studies have demonstrated that the old decompensated heart appears to maintain a functionally competent pool of CSCs during life and that the senescent phenotype of CSCs may be therefore reverted using growth factors or cardioprotective molecules. This accumulating knowledge is fundamental for the prospects of CSCs as main agents for myocardial regeneration because the majority of the patients in need of such therapy are indeed aged subjects.
During the late adulthood, the heart maintains a functionally competent CSC compartment, but the aged cardiac phenotype produces an accumulation of senescent CSCs. Aging and cellular senescence are a major hindrance to the endogenous regenerative efficacy of CSCs. However, the persistence in aged decompensated hearts of a population of functionally competent CSCs with long telomeres generates the hypothesis that endogenous CSCs may be indeed rejuvenated to regain robust regenerative potential. This population of functional yet old CSCs lacks senescent markers, expresses telomerase and cycling proteins, such as Ki67, and displays the capacity to migrate to injured zones generating a healthy progeny of young CMs. Indeed, as demonstrated in old humans, a pool of CSCs seems to maintain a growth reserve and self-renewing potential in the cardiac tissue, critical variables for effective cardiac homeostasis and repair during aging.
It is expected that a better understanding of the metabolic pathways and molecular mechanisms active in adult stem cells in old tissues may be helpful to develop genetic approaches or drugs to preserve their stemness potential during aging and to manipulate their quiescence, self-renewal, and differentiation. Several strategies able to decrease ROS levels, to restore or increase telomerase activity and telomere length in order to delay the natural aging process of the entire organism, have been studied in the past decade.
The present available evidence shows that the mammalian, including the human, myocardium possesses an "aged" CSC phenotype and this affects CSC self-renewal ability, differentiation, and regenerative potential. Thus, CSCs are not immortal. They undergo cellular aging in response to a variety of physiological and pathological demands. We can envision the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. Indeed, if CSC aging is really a stochastic cell autonomous process, then the possibility to rejuvenate the endogenous CSC population by stimulating their growth and self-renewing could be concrete. On the other hand, CSC aging could be a cell cycle-dependent process, affecting all or most of the endogenous CSC population, with a consequent irreversible loss of CSC regenerative capacity with time. If the latter is correct, it is predictable that the loss of CSC regenerative capacity with time progression is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The determination of whether the aged phenotype of the CSCs is reversible or irreversible has importance for the future of myocardial regeneration.
3-31-19
https://www.fightaging.org/archives/2019/03/on-adult-cardiac-stem-cells-and-their-aging/
Does the adult mammalian heart contain a population of stem cells capable of tissue repair? If so, they are not very active; the heart is one of the least regenerative of organs, alongside the brain and the rest of the central nervous system. Opinions and study results differ on whether or not cardiac stem cells exist in any meaningful sense in the adult heart. If they do, there is the possibility of coercing them into greater efforts in tissue maintenance. This is possibly a faster path to regeneration of a damaged or aging heart than any of the other options. However, this would also require that these stem cells not only exist, but also survive into old age in a sizable enough population to produce regeneration. This is another area of study in which there are more questions than answers.
Until the new millennium, the adult heart was considered a postmitotic organ, but several recent studies have supported the notion that it possesses a population of endogenous cardiac stem/progenitor cells (CSCs) supporting myocardial cell turnover and regeneration due to their intrinsic potential to differentiate in all cardiac cell lineages. This discovery opened a new era for myocardial regeneration where endogenous cardiac stem/progenitor cells were introduced as direct regenerative agents and/or endogenous targets of regenerative therapy to effectively replenish the heart muscle cells, lost by injury and/or age, in order to improve/normalize myocardial function.
However, the pathological and pathophysiological cardiomyopathy that occurs with age also affects the stem cell microenvironment modifying adult stem cell biology and then their ability, during lifespan, to repair damaged tissues and organs. Accordingly, as shown for other stem cell types, cardiac stem cell (CSC) potential has also been found to be compromised or even lost with aging as a consequence of the accumulation and activation of senescence factors affecting myocardial homeostasis, producing DNA damage, and alteration of the telomere-telomerase system eventually leading to a senescent phenotype of CSCs. Despite this evidence, interesting studies have demonstrated that the old decompensated heart appears to maintain a functionally competent pool of CSCs during life and that the senescent phenotype of CSCs may be therefore reverted using growth factors or cardioprotective molecules. This accumulating knowledge is fundamental for the prospects of CSCs as main agents for myocardial regeneration because the majority of the patients in need of such therapy are indeed aged subjects.
During the late adulthood, the heart maintains a functionally competent CSC compartment, but the aged cardiac phenotype produces an accumulation of senescent CSCs. Aging and cellular senescence are a major hindrance to the endogenous regenerative efficacy of CSCs. However, the persistence in aged decompensated hearts of a population of functionally competent CSCs with long telomeres generates the hypothesis that endogenous CSCs may be indeed rejuvenated to regain robust regenerative potential. This population of functional yet old CSCs lacks senescent markers, expresses telomerase and cycling proteins, such as Ki67, and displays the capacity to migrate to injured zones generating a healthy progeny of young CMs. Indeed, as demonstrated in old humans, a pool of CSCs seems to maintain a growth reserve and self-renewing potential in the cardiac tissue, critical variables for effective cardiac homeostasis and repair during aging.
It is expected that a better understanding of the metabolic pathways and molecular mechanisms active in adult stem cells in old tissues may be helpful to develop genetic approaches or drugs to preserve their stemness potential during aging and to manipulate their quiescence, self-renewal, and differentiation. Several strategies able to decrease ROS levels, to restore or increase telomerase activity and telomere length in order to delay the natural aging process of the entire organism, have been studied in the past decade.
The present available evidence shows that the mammalian, including the human, myocardium possesses an "aged" CSC phenotype and this affects CSC self-renewal ability, differentiation, and regenerative potential. Thus, CSCs are not immortal. They undergo cellular aging in response to a variety of physiological and pathological demands. We can envision the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. Indeed, if CSC aging is really a stochastic cell autonomous process, then the possibility to rejuvenate the endogenous CSC population by stimulating their growth and self-renewing could be concrete. On the other hand, CSC aging could be a cell cycle-dependent process, affecting all or most of the endogenous CSC population, with a consequent irreversible loss of CSC regenerative capacity with time. If the latter is correct, it is predictable that the loss of CSC regenerative capacity with time progression is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The determination of whether the aged phenotype of the CSCs is reversible or irreversible has importance for the future of myocardial regeneration.