Diabetes and aging alter bone marrow contributions to tissue maintenance

Bone marrow-derived cells contribute to repair of injured tissue and to the maintenance of tissue homeostasis, but the extent to which perturbations of systemic homeostasis modulate this contribution is unknown. Accordingly, hematopoietic chimeras were used to determine contributions of bone marrow-derived cells to hepatocytes, skeletal muscle myocytes, and cardiomyocytes in healthy young, healthy old, and young obese diabetic mice. Mice with multiple genomic copies of a non-expressed β-globin/pBR322 sequence served as bone marrow donors. Because detection of the integrated sequence does not involve gene expression and many copies of the sequence are present, the sensitivity of detection is high and is not influenced by the state of cell differentiation. Our data indicate that bone marrow contributes a significant fraction of hepatocytes in old and diabetic mice, but half as many in young mice. They also show that bone marrow is a significant source of new cardiomyocytes at all ages and that this contribution is unaffected by diabetes. Additionally we found that bone marrow makes a substantial contribution to skeletal myocyte replacement that decreases with age. In summary, bone marrow-derived cells contribute significantly to normal non-hematopoietic cell replacement, a contribution that is altered by overall homeostatic state in a tissue specific manner. These data are significant if we are to understand if, and if so how, bone marrow-derived cell dysfunction contributes to tissue damage and senescence.