Cell intrinsic alterations underlie hematopoietic stem cell aging

Abstract

Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.leukemia ͉ microarray ͉ ontogeny ͉ lineage potential

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

“…Aging of HSCs was thought to be primarily regulated by cell intrinsic‐driven mechanisms (Morrison et al , 1996; Rossi et al , 2005; Chambers & Goodell, 2007; Geiger et al , 2013). In this study, we demonstrate a critical role for decreased OPN in osteoblasts in aged endosteal‐enriched stroma cells for inferring aging‐associated phenotypes on HSCs, while exposing old LT‐HSCs to OPN fragments activated by thrombin results in the attenuation of aging‐associated phenotypes and function of aged HSCs.…”

“…An apolar distribution of the small RhoGTPase Cdc42 and the cytoskeletal protein tubulin within the cytosol, and of histone 4 acetylated on lysine 16 (AcH4K16) in the nucleus (Florian et al , 2012) caused by increased activity of the small RhoGTPase Cdc42, as well as additional changes in epigenetic modifications referred to as epigenetic drift and altered gene expression profiles (e.g., high expression of myeloid genes) are additional hallmarks of aged HSCs (Chambers et al , 2007; Florian & Geiger, 2010; Florian et al , 2012; Beerman et al , 2013). 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).…”

Interleukin‐21 administration to aged mice rejuvenates their peripheral T‐cell pool by triggering de novo thymopoiesis

“…While the frequency of LT‐HSCs increases drastically in the BM of ageing mice, a decrease in the ST‐HSC and the transiently reconstituting MPP populations occurs in parallel (confirmed in Fig. S2) (Rossi et al ., 2005). Such alterations are elemental to thymopoiesis as the ST‐HSC and MPP fractions both lie upstream of CLP and contribute to lymphoid reconstitution (Rossi et al ., 2005).…”

“…S2) (Rossi et al ., 2005). Such alterations are elemental to thymopoiesis as the ST‐HSC and MPP fractions both lie upstream of CLP and contribute to lymphoid reconstitution (Rossi et al ., 2005). These observations are consistent with microarray analyses revealing the existence of systematic downregulation of LT‐HSC‐specific genes mediating lymphoid specification and function with ageing (Rossi et al ., 2005).…”

“…Such alterations are elemental to thymopoiesis as the ST‐HSC and MPP fractions both lie upstream of CLP and contribute to lymphoid reconstitution (Rossi et al ., 2005). These observations are consistent with microarray analyses revealing the existence of systematic downregulation of LT‐HSC‐specific genes mediating lymphoid specification and function with ageing (Rossi et al ., 2005). This implies that rIL‐21 can compensate for deficiencies affecting BM‐derived progenitors by stimulating the expansion of progenitor cells such as ETPs that have already seeded the thymic compartment.…”