Ischemic cardiac injury is the main contributor to heart failure, and the regenerative capacity of intrinsic stem cells plays an important role in tissue repair after injury. However, stem cells in aged individuals have reduced regenerative potential and aged tissues lack the capacity to renew. Growth differentiation factor 11 (GDF11), from the activin-transforming growth factor β superfamily, has been shown to promote stem cell activity and rejuvenation. We carried out non-invasive targeted delivery of the GDF11 gene to the heart using ultrasound-targeted microbubble destruction (UTMD) and cationic microbubble (CMB) to investigate the ability of GDF11 to rejuvenate the aged heart and improve tissue regeneration after injury. Young (3 months) and old (21 months) mice were used to evaluate the expression of GDF11 mRNA in the myocardium at baseline and after ischemia/reperfusion (I/R) and myocardial infarction. GDF11 expression decreased with age and following myocardial injury. UTMD-mediated delivery of the GDF11 plasmid to the aged heart after I/R injury effectively and selectively increased GDF11 expression in the heart, and improved cardiac function and reduced infarct size. Over-expression of GDF11 decreased senescence markers, p16 and p53, as well as the number of p16 cells in old mouse hearts. Furthermore, increased proliferation of cardiac stem cell antigen 1 (Sca-1) cells and increased homing of endothelial progenitor cells and angiogenesis in old ischemic hearts occurred after GDF11 over-expression. Repetitive targeted delivery of the GDF11 gene via UTMD can rejuvenate the aged mouse heart and protect it from I/R injury.

CNPY2 is a HIF-1α-regulated, secreted angiogenic growth factor that promotes SMC migration, proliferation, and tissue revascularization. This new target may have a broader profile than currently available proteins.

No abstract

Bone marrow (BM) reconstitution with young BM cells in aged recipients restores the functionality of cardiac resident BM-derived progenitors. This study investigated the cell type primarily responsible for this effect. We reconstituted old mice with BM cells from young or old mice and found that the number of stem cell antigen 1 (Sca-1) cells homing to the heart was significantly greater in young than old chimeras. We then reconstituted old mice with young BM Sca-1+ or Sca-1− cells. We found that Sca-1 cells repopulated the recipient BM and homed to the heart. The number of BM-derived cells in the aged myocardium co-expressing PDGFRβ was 3 times greater in Sca-1+ than Sca-1− chimeric mice. Sca-1+ chimeras had more active cell proliferation in the infarcted heart and improved ventricular function after MI. The improved regeneration involved activation of the PDGFRβ/Akt/p27Kip1 pathway. Sca-1+ stem cells rejuvenated cardiac tissue in aged mice. Restoration of the Sca-1+ subset of stem cells by BM reconstitution improved cardiac tissue regeneration after injury in aged mice.

Visual Abstract

Retinal ganglion cell apoptosis and optic nerve degeneration are prevalent in aged patients, which may be related to the decrease in bone marrow (BM) stem cell number/function because of the possible cross‐talk between the two organs. This pathological process is accelerated by retinal ischaemia‐reperfusion (I/R) injury. This study investigated whether young BM stem cells can regenerate and repair the aged retina after acute I/R injury. Young BM stem cell antigen 1 positive (Sca‐1+) or Sca‐1− cells were transplanted into lethally irradiated aged recipient mice to generate Sca‐1+ and Sca‐1− chimaeras, respectively. The animals were housed for 3 months to allow the young Sca‐1 cells to repopulate in the BM of aged mice. Retinal I/R was then induced by elevation of intraocular pressure. Better preservation of visual function was found in Sca‐1+ than Sca‐1− chimaeras 7 days after injury. More Sca‐1+ cells homed to the retina than Sca‐1− cells and more cells differentiated into glial and microglial cells in the Sca‐1+ chimaeras. After injury, Sca‐1+ cells in the retina reduced host cellular apoptosis, which was associated with higher expression of fibroblast growth factor 2 (FGF2) in the Sca‐1+ chimaeras. Young Sca‐1+ cells repopulated the stem cells in the aged retina and diminished cellular apoptosis after acute I/R injury through FGF2 and Akt signalling pathways.

ABSTRACT.Purpose: To investigate the prevalence and causes of visual impairment in a rural population in north-east China. Methods: A population-based study was conducted within Bin County, Harbin of north-east China. Low vision and blindness were defined using the World Health Organization categories of visual impairment. The prevalence of visual impairment was estimated, and causes were identified based on best-corrected visual acuity (BCVA) as well as presenting visual acuity (VA). Results: Out of 5764 people, 4956 (86.01%) aged older than 40 participated in the study. The prevalence of visual impairment, low vision and blindness based on presenting VA was 9.6% (BCVA, 6.6%), 7.7% (BCVA, 4.9%) and 1.9% (BCVA, 1.7%), respectively. Taking the presenting VA, cataract (44%) was the most common cause for visual impairment followed by uncorrected refractive error (24%), treatable causes of visual impairment accounted for 68% of the total cases. Cataract (59%) and glaucoma (15%) were leading causes for blindness based on presenting VA. According to BCVA, cataract was the leading cause of visual impairment and blindness (58% and 60%, respectively), followed by glaucoma (17% and 15%, respectively). The prevalence of visual impairment was higher among women than men (p < 0.0001) and increasing with age (p < 0.0001) and decreasing with increasing education level (p = 0.0075). Conclusion: Visual impairment was a serious public health problem in this rural population, with most of it easily remedied. Results highlighted the need for visual impairment prevention programs to an increasing number of elderly people, with a special emphasis on female and those with little or no education.

Reduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca‐1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca‐1+ or Sca‐1− cells from young (2–3 months) or aged (18–19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca‐1+, young Sca‐1−, old Sca‐1+, and old Sca‐1−. Four months later, expression of rejuvenation‐related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase‐related protein (DNA‐PKcs, TRF‐2) expression, whereas expression of senescence‐related genes (p16INK4a, P19ARF, p27Kip1) and proteins (p16INK4a, p27Kip1) was decreased in Sca‐1+ chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP−CD31+) but not cardiomyocytes were the primary cell type rejuvenated by young Sca‐1+ cells as shown by improved proliferation, migration, and tubular formation abilities. C‐X‐C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP+) cells isolated from young Sca‐1+ chimeric hearts. Protein expression of Cxcr4, phospho‐Akt, and phospho‐FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca‐1+ group. Reconstitution of aged BM with young Sca‐1+ cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells.