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Aging Effects on Cardiac Progenitor Cell Physiology

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ABSTRACT

Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self‐renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy. © 2015 American Physiological Society. Compr Physiol 5:1775‐1814, 2015.

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Figure 1. Figure 1. Schematic representation of the major determinants of cellular and tissue aging. (A) Cellular senescence is mediated by several factors, including accumulation of cytoplasmic proteins, and alterations at the epigenetic and genomic DNA levels. These aspects, which are discussed in the text, are employed for the characterization of cellular age. SA‐β‐GAL, senescence‐associated β‐galactosidase; SAHF, senescence‐associated heterochromatin foci; SASP, senescence‐associated secretory phenotype; PML‐NBs, promyelocytic leukemia protein nuclear bodies; DDR, DNA damage response. (B) Effective removal of senescent cells induces the formation of new functionally competent cells with restoration of the steady state of the organ. However, this process is largely inefficient in old and pathologic tissues, leading to the accumulation of senescent cells, conditions the age of the organ and its performance.
Figure 2. Figure 2. Schematic representation of the telomerase‐telomere system. (A, B) The formation of D‐loops and T‐loops prevents the recognition of telomeres as DNA lesions. Telomere dysfunction may depend on the loss of the shelterin protein complex (A) and DNA erosion, which occurs as a consequence of cell division and oxidative stress (B).
Figure 3. Figure 3. Old hCPCs and replicative senescence. (A, B) Primary cultures of actively growing human CPCs (young) were subjected to serial passages (replicative senescence: old), or to doxorubicin exposure (stress‐induced senescence: old). Young and old human CPCs express c‐kit (green). Nuclei are stained with DAPI (blue). The expression of Ki67 (A: red) decreases and p16INK4a (B: red) increases in old human CPCs. Data are mean ± SD. Replicative senescence: *P = 0.009, P = 0.04; stress‐induced senescence: *P < 0.0001, P = 0.04 (adapted, with permission, from 118).
Figure 4. Figure 4. Old human CPCs and DNA damage. (A) DNA‐damage response (DDR) foci are identified in young (left) and old (right) hCPCs by coimmunolabeling for γH2A.X (green) and 53BP1 (red). Rectangles define areas illustrated at higher magnification in the insets. Phalloidin (gray) identifies the body of the cells. (B) Only hCPCs with ≥ 2 γH2A.X foci were included in the quantitative analysis. The percentage of hCPCs positive for γH2A.X foci increases in old hCPCs. Data are mean ± SD. Replicative senescence: §P = 0.02; Stress‐induced senescence: §P = 0.03 [from 118].
Figure 5. Figure 5. Schematic representation of CPC niches in the myocardium. The compartment of cardiac niches is functionally heterogeneous. In quiescent niches, the rarely dividing and highly undifferentiated state of CPCs is preserved. In active niches, CPCs undergo frequent asymmetric replication with formation of a daughter stem cell (self‐renewal) and a daughter cell committed to the myocyte fate.
Figure 6. Figure 6. In vivo inhibition of Notch 1 function induces a dilated myopathy. (A, B) B‐mode and M‐mode echocardiography of vehicle (left) and γ‐secretase inhibitor‐injected (right) mice. (C, D) γ‐Secretase inhibition leads to ventricular dilation, depressed fractional shortening and ejection fraction (C), and increased mortality (D). (E) With respect to a control heart (left panel), ventricular dilation and wall thinning are apparent in mice in which the Notch pathway was inhibited by administration of a γ‐secretase inhibitor (central and right panels). (F) Effects of γ‐secretase inhibition on cardiac anatomy. Results are mean ± SD *P < 0.05 (adapted, with permission, from 329).
Figure 7. Figure 7. Aging and wall stress. Changes in transmural circumferential wall stress during cardiac cycle as a function of age in 4‐, 12‐, 20‐, and 29‐month‐old male Fischer 344 rats. The total duration of stress for 4‐, 12‐, 20‐, and 29‐month‐old hearts was 1.1 × 106, 1.8 × 106, 2.6 × 106, and 3.9 × 106 cubic units, respectively. ENDO, endocardium; EPI, epicardium (adapted, with permission, from 57).
Figure 8. Figure 8. Aging and myocyte number in the human heart. (A, B) Effects of aging on the relative proportion of mononucleated (A) and binucleated (B) ventricular myocytes in women and men (adapted, with permission, from 247).
Figure 9. Figure 9. Aging and myocyte number. The bar graphs show aggregate number of myocyte nuclei in the left and right ventricles. Results are mean ± SD. *P < 0.05 versus the corresponding value in 4‐month‐old rats. ***P < 0.05 versus the corresponding value in 12‐month‐old rats. ****P < 0.05 versus the corresponding value in 20‐month‐old rats (adapted, with permission, from 14).
Figure 10. Figure 10. Acute and chronic myocardial infarcts. (A, B) Myocardial infarcts incompatible with survival. The large transverse myocardial sections illustrate the left ventricle (LV), interventricular septum (IS), and right ventricle (RV). Tissue necrosis is present in a large portion of the IS and in some areas of the anterior aspect of LV (arrowheads). Foci of myocardial scarring are also detected (*) (adapted, with permission, from 251). (C, D) Explanted heart in a patient undergoing cardiac transplantation. The large transverse myocardial sections illustrate a healed myocardial infarct with thinning of the wall (C, arrowheads) and multiple sites of replacement fibrosis in the noninfarcted viable tissue (D, arrowheads) (adapted, with permission, from 35).
Figure 11. Figure 11. Depressed Ca2+ transients in myocytes from the ischemic failing heart. Ca2+ transient properties in myocytes obtained from the heart of sham operated Sprague‐Dawley rats and rats subjected to coronary artery narrowing (CAN). Results are mean ± SD. *P < 0.05 (adapted, with permission, from 56).
Figure 12. Figure 12. Schematic representation of the components of cardiac niches. The niche resembles a randomly oriented ellipsoid structure located in an ill‐defined region of the interstitium. Within the niches, lineage‐negative CSCs are typically located in the center of the niches and are clustered together with early committed cells, progenitors, and precursors. Myocyte progenitors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors, GATA‐4, Nkx2.5, and MEF2C, in the absence of specific cytoplasmic proteins. Myocyte precursors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors together with cytoplasmic distribution of contractile proteins. Cells within the niches are connected by gap junctions. The extracellular matrix surrounding the niche is composed of several proteins, mostly fibronectin and α2 chain of laminin (adapted, with permission, from 194).
Figure 13. Figure 13. Connexin 43 in the human myocardium. Connexin 43 (white) defines the boundaries of cardiomyocytes (α‐SA, red). Nuclei are stained by DAPI, blue.
Figure 14. Figure 14. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 15. Figure 15. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 16. Figure 16. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 17. Figure 17. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 18. Figure 18. Properties of hypoxic and normoxic CPCs, and cardiomyocytes in the young and old mouse heart. (A) Hypoxic CPCs were recognized by positivity for the hypoxic probe pimonidazole. The distribution of telomere length is shown in hypoxic Pimonidazole‐positive (Pimopos) and normoxic Pimonidazole‐negative (Pimoneg) CPCs, and myocytes from young and old mice (adapted, with permission, from 282). (B) The preservation of CPC number within the niches may depend on the classic modality of self‐renewal or on a process of population replacement. In the first case (left), each niche constitutes an independent unit controlled by asymmetric division of CPCs with formation of a daughter stem cell that is retained within the niche and a daughter committed cell that leaves the niche area. In the second case (right), population replacement involves a mutual feedback between hypoxic and normoxic niches with exchange of primitive cells, replenishing depleted or dysfunctional niches.
Figure 19. Figure 19. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. *P < 0.05 versus BrdU‐neg myocytes, **P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).
Figure 20. Figure 20. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. *P < 0.05 versus BrdU‐neg myocytes, **P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).
Figure 21. Figure 21. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,†P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).
Figure 22. Figure 22. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,†P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).
Figure 23. Figure 23. Schematic representation of the IGF‐1‐Akt‐telomerase axis. Mouse model in which the expression of insulin‐like growth factor 1 (IGF‐1) is driven by the myocyte restricted α‐myosin heavy chain (α‐MHC) promoter. Binding of IGF‐1 to the IGF‐1 receptor (IGF‐1R) results in phosphorylation of PI‐3 kinase (PI3K), which, in turn, phosphorylates and activates Akt kinase. Phosphorylated Akt binds to a consensus site in the telomerase protein enhancing its catalytic activity and promoting telomere elongation.
Figure 24. Figure 24. Nuclear targeted Akt and myocyte mechanics. (A) Traces of unloaded myocyte shortening at 1‐Hz pacing rate. (B) Average parameters of myocyte contraction for wild‐type mice (WT) and mice overexpressing α‐MHC‐nuclear Akt (TG) are shown as mean ± SEM. (C) Ca2+ transients in myocytes paced at 1 Hz and superimposed traces. (D) Ca2+ transient properties for WT and TG are shown as mean ± SEM (adapted, with permission, from 273).
Figure 25. Figure 25. Schematic representation of the effects of stromal‐derived factor 1 (SDF‐1) on CPCs. Myocardial ischemia is characterized by an increased expression of SDF‐1, which binds to CXCR4 in CPCs promoting their migration from the niches and homing in the border zone. Activation of the SDF‐1‐CXCR4 system in CPCs results in engraftment and proliferation of CPCs in proximity of the infarct, ultimately promoting vascular regeneration.


Figure 1. Schematic representation of the major determinants of cellular and tissue aging. (A) Cellular senescence is mediated by several factors, including accumulation of cytoplasmic proteins, and alterations at the epigenetic and genomic DNA levels. These aspects, which are discussed in the text, are employed for the characterization of cellular age. SA‐β‐GAL, senescence‐associated β‐galactosidase; SAHF, senescence‐associated heterochromatin foci; SASP, senescence‐associated secretory phenotype; PML‐NBs, promyelocytic leukemia protein nuclear bodies; DDR, DNA damage response. (B) Effective removal of senescent cells induces the formation of new functionally competent cells with restoration of the steady state of the organ. However, this process is largely inefficient in old and pathologic tissues, leading to the accumulation of senescent cells, conditions the age of the organ and its performance.


Figure 2. Schematic representation of the telomerase‐telomere system. (A, B) The formation of D‐loops and T‐loops prevents the recognition of telomeres as DNA lesions. Telomere dysfunction may depend on the loss of the shelterin protein complex (A) and DNA erosion, which occurs as a consequence of cell division and oxidative stress (B).


Figure 3. Old hCPCs and replicative senescence. (A, B) Primary cultures of actively growing human CPCs (young) were subjected to serial passages (replicative senescence: old), or to doxorubicin exposure (stress‐induced senescence: old). Young and old human CPCs express c‐kit (green). Nuclei are stained with DAPI (blue). The expression of Ki67 (A: red) decreases and p16INK4a (B: red) increases in old human CPCs. Data are mean ± SD. Replicative senescence: *P = 0.009, P = 0.04; stress‐induced senescence: *P < 0.0001, P = 0.04 (adapted, with permission, from 118).


Figure 4. Old human CPCs and DNA damage. (A) DNA‐damage response (DDR) foci are identified in young (left) and old (right) hCPCs by coimmunolabeling for γH2A.X (green) and 53BP1 (red). Rectangles define areas illustrated at higher magnification in the insets. Phalloidin (gray) identifies the body of the cells. (B) Only hCPCs with ≥ 2 γH2A.X foci were included in the quantitative analysis. The percentage of hCPCs positive for γH2A.X foci increases in old hCPCs. Data are mean ± SD. Replicative senescence: §P = 0.02; Stress‐induced senescence: §P = 0.03 [from 118].


Figure 5. Schematic representation of CPC niches in the myocardium. The compartment of cardiac niches is functionally heterogeneous. In quiescent niches, the rarely dividing and highly undifferentiated state of CPCs is preserved. In active niches, CPCs undergo frequent asymmetric replication with formation of a daughter stem cell (self‐renewal) and a daughter cell committed to the myocyte fate.


Figure 6. In vivo inhibition of Notch 1 function induces a dilated myopathy. (A, B) B‐mode and M‐mode echocardiography of vehicle (left) and γ‐secretase inhibitor‐injected (right) mice. (C, D) γ‐Secretase inhibition leads to ventricular dilation, depressed fractional shortening and ejection fraction (C), and increased mortality (D). (E) With respect to a control heart (left panel), ventricular dilation and wall thinning are apparent in mice in which the Notch pathway was inhibited by administration of a γ‐secretase inhibitor (central and right panels). (F) Effects of γ‐secretase inhibition on cardiac anatomy. Results are mean ± SD *P < 0.05 (adapted, with permission, from 329).


Figure 7. Aging and wall stress. Changes in transmural circumferential wall stress during cardiac cycle as a function of age in 4‐, 12‐, 20‐, and 29‐month‐old male Fischer 344 rats. The total duration of stress for 4‐, 12‐, 20‐, and 29‐month‐old hearts was 1.1 × 106, 1.8 × 106, 2.6 × 106, and 3.9 × 106 cubic units, respectively. ENDO, endocardium; EPI, epicardium (adapted, with permission, from 57).


Figure 8. Aging and myocyte number in the human heart. (A, B) Effects of aging on the relative proportion of mononucleated (A) and binucleated (B) ventricular myocytes in women and men (adapted, with permission, from 247).


Figure 9. Aging and myocyte number. The bar graphs show aggregate number of myocyte nuclei in the left and right ventricles. Results are mean ± SD. *P < 0.05 versus the corresponding value in 4‐month‐old rats. ***P < 0.05 versus the corresponding value in 12‐month‐old rats. ****P < 0.05 versus the corresponding value in 20‐month‐old rats (adapted, with permission, from 14).


Figure 10. Acute and chronic myocardial infarcts. (A, B) Myocardial infarcts incompatible with survival. The large transverse myocardial sections illustrate the left ventricle (LV), interventricular septum (IS), and right ventricle (RV). Tissue necrosis is present in a large portion of the IS and in some areas of the anterior aspect of LV (arrowheads). Foci of myocardial scarring are also detected (*) (adapted, with permission, from 251). (C, D) Explanted heart in a patient undergoing cardiac transplantation. The large transverse myocardial sections illustrate a healed myocardial infarct with thinning of the wall (C, arrowheads) and multiple sites of replacement fibrosis in the noninfarcted viable tissue (D, arrowheads) (adapted, with permission, from 35).


Figure 11. Depressed Ca2+ transients in myocytes from the ischemic failing heart. Ca2+ transient properties in myocytes obtained from the heart of sham operated Sprague‐Dawley rats and rats subjected to coronary artery narrowing (CAN). Results are mean ± SD. *P < 0.05 (adapted, with permission, from 56).


Figure 12. Schematic representation of the components of cardiac niches. The niche resembles a randomly oriented ellipsoid structure located in an ill‐defined region of the interstitium. Within the niches, lineage‐negative CSCs are typically located in the center of the niches and are clustered together with early committed cells, progenitors, and precursors. Myocyte progenitors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors, GATA‐4, Nkx2.5, and MEF2C, in the absence of specific cytoplasmic proteins. Myocyte precursors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors together with cytoplasmic distribution of contractile proteins. Cells within the niches are connected by gap junctions. The extracellular matrix surrounding the niche is composed of several proteins, mostly fibronectin and α2 chain of laminin (adapted, with permission, from 194).


Figure 13. Connexin 43 in the human myocardium. Connexin 43 (white) defines the boundaries of cardiomyocytes (α‐SA, red). Nuclei are stained by DAPI, blue.


Figure 14. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 15. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 16. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 17. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 18. Properties of hypoxic and normoxic CPCs, and cardiomyocytes in the young and old mouse heart. (A) Hypoxic CPCs were recognized by positivity for the hypoxic probe pimonidazole. The distribution of telomere length is shown in hypoxic Pimonidazole‐positive (Pimopos) and normoxic Pimonidazole‐negative (Pimoneg) CPCs, and myocytes from young and old mice (adapted, with permission, from 282). (B) The preservation of CPC number within the niches may depend on the classic modality of self‐renewal or on a process of population replacement. In the first case (left), each niche constitutes an independent unit controlled by asymmetric division of CPCs with formation of a daughter stem cell that is retained within the niche and a daughter committed cell that leaves the niche area. In the second case (right), population replacement involves a mutual feedback between hypoxic and normoxic niches with exchange of primitive cells, replenishing depleted or dysfunctional niches.


Figure 19. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. *P < 0.05 versus BrdU‐neg myocytes, **P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).


Figure 20. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. *P < 0.05 versus BrdU‐neg myocytes, **P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. *P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).


Figure 21. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,†P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).


Figure 22. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,†P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).


Figure 23. Schematic representation of the IGF‐1‐Akt‐telomerase axis. Mouse model in which the expression of insulin‐like growth factor 1 (IGF‐1) is driven by the myocyte restricted α‐myosin heavy chain (α‐MHC) promoter. Binding of IGF‐1 to the IGF‐1 receptor (IGF‐1R) results in phosphorylation of PI‐3 kinase (PI3K), which, in turn, phosphorylates and activates Akt kinase. Phosphorylated Akt binds to a consensus site in the telomerase protein enhancing its catalytic activity and promoting telomere elongation.


Figure 24. Nuclear targeted Akt and myocyte mechanics. (A) Traces of unloaded myocyte shortening at 1‐Hz pacing rate. (B) Average parameters of myocyte contraction for wild‐type mice (WT) and mice overexpressing α‐MHC‐nuclear Akt (TG) are shown as mean ± SEM. (C) Ca2+ transients in myocytes paced at 1 Hz and superimposed traces. (D) Ca2+ transient properties for WT and TG are shown as mean ± SEM (adapted, with permission, from 273).


Figure 25. Schematic representation of the effects of stromal‐derived factor 1 (SDF‐1) on CPCs. Myocardial ischemia is characterized by an increased expression of SDF‐1, which binds to CXCR4 in CPCs promoting their migration from the niches and homing in the border zone. Activation of the SDF‐1‐CXCR4 system in CPCs results in engraftment and proliferation of CPCs in proximity of the infarct, ultimately promoting vascular regeneration.
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Marcello Rota, Polina Goichberg, Piero Anversa, Annarosa Leri. Aging Effects on Cardiac Progenitor Cell Physiology. Compr Physiol 2015, 5: 1775-1814. doi: 10.1002/cphy.c140082