Impaired Hematopoietic Stem Cell Functioning After Serial Transplantation and During Normal Aging

Abstract

Adult somatic stem cells possess extensive self-renewal capacity, as their primary role is to replenish aged and functionally impaired tissues. We have previously shown that the stem cell pool in short-lived DBA/2 (D2) mice is reduced during aging, in contrast to longlived C57BL/6 (B6) mice. This suggests the existence of a genetically determined mitotic clock operating in stem cells, which possibly limits organismal aging. In the study reported here, unfractionated bone marrow (BM) cells or highly purified Lin -Sca-1 + c-kit + (LSK) cells were serially transplanted in lethally irradiated D2 and B6 mice. In both strains, serial transplantation resulted in a substantial loss of stem cell activity. However, as we estimate that in B6 mice, the maximum number of population doublings of primitive cells is approximately 30, in D2 mice this is only approximately 20, resulting in a 1,000-fold difference in expansion potential, irrespective of whether whole bone marrow or purified hematopoietic stem cells (HSCs) were transplanted. Interestingly, recipients reconstituted with serially transplanted BM cells were able to accept a freshly isolated graft without any further conditioning. Finally, we show that whereas transplantation of BM cells into healthy, nonconditioned, young B6 recipients does not lead to engraftment, young BM cells do engraft and provide multilineage reconstitution in nonirradiated aged mice. Our data clearly establish the relevance of an intrinsic, genetically controlled program associated with impaired stem cell functioning during aging. Stem Cells 2005;23:82-92

Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia

“…Poor engraftment with older donors has also been shown in murine transplant models, 5,6 and this kind of "aging" in grafts from older donors may be related to ageassociated modifications in DNA methylation patterns 29 and/or shorter length of telomeres in hematopoietic stem or progenitor cells from older donors.…”

“…[2][3][4] In addition to these, biological speculation from previous published studies regarding hematopoietic stem cell repopulation and donor-derived T-cell function have suggested that transplantation from older donors may result in a higher incidence of engraftment failure and acute GvHD (aGvHD), and, as a result, increase transplant-related death and lead to inferior OS. According to murine studies, hematopoietic stem cells from older donors do not re-populate as efficiently, 5,6 and grafts from older donors have a higher ratio of memory T cells to naïve T cells; 7 an increase in peripheral blood memory T cells has been shown to be related to the occurrence of aGvHD in humans. 8,9 The influence of donor age in unrelated hematopoietic cell transplantation has long been discussed in various studies, and some have shown a relationship between older donor and worse prognosis.…”

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). Aged HSCs also give rise to more cells of myeloid lineage at the expense of lymphoid fates (Sudo et al, 2000;Kim et al, 2003;Rossi et al, 2005;Cho et al, 2008;Guerrettaz et al, 2008).…”

Estradiol increases hematopoietic stem and progenitor cells independent of its actions on bone

“…Serial transplantation was performed as described 17 using CD45.1 recipients receiving 5¥10 6 BM cells from either control or estradiol treated mice. Four months posttransplantation, recipients were analyzed and 5¥10 6 BM cells were transplanted into secondary or third recipients.…”