Lataillade et al

Lataillade et al. ability of HSCs in G1 phase to engraft to irradiated recipients is definitely lost in adult bone marrow. (D) Administration of the CXCL12/CXCR4 antagonist SDF-1G2 into recipient mice prior to transplantation enables S/G2/M HSCs from fetal liver, postnatal bone marrow, and possibly (question mark) adult bone marrow to engraft in recipient mice. Bowie et al. (6) suggest a correlation of this abrupt switch in cycling status and engraftment ability of postnatal hematopoiesis with that of specific telomere shortening in human being children 5 years of age or 5(6)-TAMRA older compared with infants or toddlers (12). This is of importance, since the maintenance of telomere size is vital to cell self renewal, and HSCs express high levels of telomerase, a cellular reverse transcriptase that stabilizes telomere size (13). In addition, telomere size has been observed to decrease with repeated HSC transplantation (14), and HSCs from mice with targeted disruption of the telomere-maintenance gene undergo premature senescence (15). Blockade of the CXCL12/CXCR4 connection reverses the lack of engrafting potential of S/G2/M HSCs 5(6)-TAMRA Although several signaling pathways have been identified that impact the proliferation of HSCs, multiple efforts to increase the stem cell populace in vitro have been largely unsuccessful. In part, this may reflect inadequate recapitulation of the microenvironment-associated cell-cell interactions that were shown nearly 3 decades ago to be important for HSC fate (16). Thus, stem cell division in ex lover vivo systems that lack authentic hematopoietic microenvironmental cues is usually most often accompanied by proliferation that leads to stem cell differentiation. More recently, new strategies that lead to apparently improved HSC growth ex lover vivo, albeit at generally modest levels, have been explained (examined in ref. 17). These strategies include the use of more refined cytokine combinations using (that have) proteins favoring HSC proliferation 5(6)-TAMRA with less differentiation; the blockading of signaling pathways such as TGF-; the inhibition of cyclin-dependent kinase Rabbit Polyclonal to NFAT5/TonEBP (phospho-Ser155) inhibitors p21Cip1/Waf1 and p27Kip1; the inhibition of dipeptidase CD26 or Rho GTPases; the enhanced expression or function of HoxB4, Notch, or -catenin pathways; and the modification of the hematopoietic microenvironment by overexpression or infusion of osteoblast-acting parathormone. In addition, Bowie et al. (6) show that expression of CXC chemokine ligand 12 (CXCL12, also referred to as stromal cellCderived factor 1 [SDF-1]) is usually increased in HSCs during cell cycling. Lataillade et al. (18) previously suggested that HSC expression of CXCL12 suppressed apoptosis and promoted cell-cycle transition via an autocrine/paracine mechanism. CXCL12 is usually thought to act as a pivotal chemoattractant of HSCs through CXC chemokine receptor 4 (CXCR4) within the bone marrow microenvironment. Moreover, Bowie et al. show that pretransplant administration of SDF-1G2, an antagonist of CXCL12/CXCR4 conversation, reversed the engraftment defect of HSCs in S/G2/M during transplantation (Physique ?(Physique11 and ref. 6). These findings might suggest that the microlocalization of transplanted HSCs to specific bone marrow niches which may be needed to activate a self-renewal program depends on the strength of the CXCL12 gradient the cells encounter within the bone marrow space. Notably, this blockade of CXCL12/CXCR4 conversation by SDF-1G2 administered intravenously appears to take action only in the peripheral blood, while sparing the bone marrow. The authors therefore speculate that this overexpression of CXCL12 by cycling HSCs may interfere in the response of HSCs to an intramedullary gradient of CXCL12 and thus prevent their self renewal, leading to differentiation, apoptosis, or sequestration of 5(6)-TAMRA these cells in anatomic sites that do not support hematopoiesis. An intriguing possibility raised by the authors is usually that timed CXCR4 transmission blockade (for instance, by using the clinically available drug AMD3100) or an increase of CXCL12 levels in the medullary space may transiently restore an effective chemoattractant gradient for the HSCs in S/G2/M and favor the lodging of HSCs normally insensitive to the CXCL12 gradient in the marrow microenvironment. If true, this approach would have important therapeutic applications to increase the efficiency of HSC engraftment in settings where the number and/or quality of these cells are limited. Examples of this include the use of umbilical cord blood for stem cell transplantation in adults and the engraftment of gene-corrected HSC populations following ex lover vivo manipulations required by current vector transduction protocols. The findings explained by Bowie et al. (6) that HSCs from adults differ from those of newborns open new areas of research aimed at defining the cell and molecular determinants of the switch in cycling characteristics between postnatal and adult HSCs..