1. Long-term repopulation of aged bone marrow stem cells using young Sca-1 cells promotes aged heart rejuvenation.
- Author
-
Li J, Li SH, Dong J, Alibhai FJ, Zhang C, Shao ZB, Song HF, He S, Yin WJ, Wu J, Weisel RD, Liu SM, and Li RK
- Subjects
- Animals, Bone Marrow Cells metabolism, Cellular Senescence, Female, Mice, Mice, Inbred C57BL, Mice, Transgenic, Antigens, Ly metabolism, Heart, Membrane Proteins metabolism, Rejuvenation
- Abstract
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., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)- Published
- 2019
- Full Text
- View/download PDF