Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells

Abstract

To test the hypothesis that aging has negative effects on stem-cell homing and engraftment, young or old C57BL/6 bone marrow (BM) cells were injected, using a limiting-dilution, competitive transplantation method, into old or young Ly5 congenic mice. Numbers of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) recovered from BM or spleen were measured and compared with the numbers initially transplanted. Although the frequency of marrow competitive repopulation units (CRUs) increased approximately 2-fold from 2 months to 2 years of age, the BM homing efficiency of old CRUs was approximately 3-fold lower than that of young CRUs. Surprisingly, the overall size of individual stem-cell clones generated in recipients receiving a single CRU was not affected by donor age.

Gene expression changes in normal haematopoietic cells

“…16,132 Despite these findings (or perhaps due to this dysfunction) older mice have an increased number of HSCs, although these cells demonstrate reduced repopulating potential and a propensity towards myeloid skewing. 108,[133][134][135] Together, these findings strongly support the conclusion that aging expands one or more pools of dysfunctional HPCs/HSCs that limit the hematopoietic system response, especially in times of stress. Since DNA repair processes are disrupted with aging, DNA damage accumulates in the cells of older adults.…”

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

“…Historically, aging of HSCs was thought to be solely influenced by stem cell intrinsic mechanisms (Rossi et al , 2005; Florian et al , 2012). Novel data though imply also the HSC niche in driving or exacerbating aging of HSC (Li et al , 2001; Liang et al , 2005; Zhu et al , 2007). Elucidation of the mechanisms by which aging of the niche affects HSC aging will support the design of rationale therapeutic interventions to attenuate aging in hematopoiesis (Khong et al , 2015; Khatri et al , 2016).…”

Epigenetic regulation of aging stem cells

“…HSCs isolated from older mice show defects in mobilization and homing to bone marrow (Morrison et al, 1996;Kim et al, 2003;Liang et al, 2005;Xing et al, 2006). In competitive transplantation assays, a rigorous test for both self-renewal and multipotency during which donor HSCs are co-injected with wild-type bone marrow and assessed for their ability to regenerate all blood lineages, aged HSCs shows defect in long-term reconstitution of the immune system (Sudo et al, 2000;Kamminga et al, 2005;Rossi et al, 2005;Chambers et al, 2007).…”