CD34+ cells from mobilized peripheral blood retain fetal bone marrow repopulating capacity within the Thy-1+ subset following cell division ex vivo

Young, Judy; Lin, Karen; Hansteen, Gun; Travis, Marilyn; Murray, Lesley J.; Jaing, Li; Scollay, Roland; Hill, Beth

doi:10.1016/s0301-472x(99)00030-2

Cited by 27 publications

(21 citation statements)

References 34 publications

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“…5,6,9,43 The residual marrow-repopulating potential of such ex vivo generated grafts has been reported to reside either within a population of HSCs that had either remained quiescent or had undergone a limited numbers of divisions. [58][59][60] In the present studies, we confirm CB CD34 ϩ CD90 ϩ cells that have undergone 5 to 10 cell divisions in vitro in response to a cytokine combination lack in vivo marrow-repopulating potential. By contrast, CD34 ϩ CD90 ϩ cells exposed to 5azaD/TSA, which also had undergone 5 to 10 cell divisions, still contained assayable SRCs.…”

Section: Discussionsupporting

confidence: 72%

Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

Araki

Yoshinaga

Boccuni

et al. 2006

Blood

109

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Section: Discussionsupporting

confidence: 72%

Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

Araki

Yoshinaga

Boccuni

et al. 2006

Blood

109

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Section: Introductionmentioning

confidence: 56%

“…20,21 It has also allowed cell proliferation to be correlated with retention of primitive phenotypes and functions (cobblestone area-forming cells and NOD-SCID repopulation) by primitive progenitors exposed to cytokines for a short period. 18,19 These data have confirmed that actively proliferating cells can retain LTC-IC or NOD-SCID-rc functions, but only transiently.Others and we [22][23][24][25] have reported that murine stromal cells can counteract the loss of stem cell activity of human bone marrow CD34 ϩ CD38 low/neg samples exposed to high concentrations of cytokines. However, it remains unresolved whether this effect of stromal For personal use only.…”

mentioning

confidence: 56%

Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history

Bennaceur‐Griscelli

Pondarré

Schiavon

et al. 2001

Blood

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Stem cell proliferation induced by potent cytokines usually leads to a loss of primitive potential through differentiation. In this study, the ability of cytokines and murine MS5 stromal cells to independently regulate the proliferation and longterm culture-initiating cell (LTC-IC) activity of primitive CD34 ؉ CD38 low/neg human bone marrow cells was evaluated. To compare populations with identical proliferation histories, cells were labeled with carboxy fluorescein diacetate succinimidyl ester, and LTC-IC activity was as- IntroductionThe loss of stem cell activity that invariably occurs when primitive cells are induced to divide by cytokines compromises attempts to obtain a net increase in the number of stem cells for therapeutic purposes in transplantation or gene transfer with murine retroviral vectors. What can be demonstrated is an amplification of cells retaining similar functional properties, such as the ability to reconstitute long-term culture (LTC) in vitro 1 or nonobese diabeticsevere combined immunodeficient (NOD-SCID) recipients in vivo. 2,3 However, this is by no means proof of self-renewal because the molecular identities of daughter and parent cells cannot be demonstrated in the absence of known genetic mechanisms that control self-renewal versus differentiation. Thus, net increases in the number of long-term culture-initiating cell, (LTC-IC), human NOD-SCID-reconstituting cells (rc), and, more rarely, murine long-term repopulating cells 4 have been described after a shortterm exposure to cytokines, but usually the expansion does not exceed a factor of 10, and the low frequency of proliferating cells participating in the expansion of the stem cell compartment also complicates evaluation of quantitative analyses of these responses.Although stromal cells have been assigned contradictory functions, they have often been viewed as important for the maintenance of primitive progenitor activity, 5 particularly in the lymphoid lineages. 6 Coculture with stromal cells is the basis of the LTC system. However, now that many purified cytokines are available, several groups have demonstrated an additional ability of stromal feeders to maintain primitive hematopoietic cell function in cultures used for expansion [7][8][9] or gene transfer protocols. 10 The contribution of cytokines, adhesion molecules, 11 and other stromaderived regulators, such as Notch ligands, 12 in these effects has been reported, though it is unclear whether stromal cells act by affecting cell survival 13 or by promoting or delaying cell-cycle entry. 14 One helpful strategy to monitor variations in cell proliferation in these conditions has been to label the cells with fluorescent dyes such as PKH-2, PKH-26, 15 or more recently carboxy fluorescein diacetate succinimidyl ester (CFSE). [16][17][18][19] Because these dyes are diluted by cell division, they can be used to track the proliferative behavior of cells in vitro and are thus useful to correlate changes in cell function with successive cell divisions. This approach has been used rec...

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“…Stochastic HSC behavior in vivo may ensure the relative protection of a proportion of stem cells from the burden of HSCT-induced replicative stress. With ex vivo culture techniques capable of inducing proliferation of all repopulating cells in a very short space of time, 59 we must be careful not to overly stress an entire population of HSCs before it has begun its work in a myeloablated recipient. Markers of HSC replicative stress should be monitored very closely in this setting.…”

Section: Early Hematopoietic Reconstitution After Hsct 2393mentioning

confidence: 99%

Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss

Thornley

Sutherland

Wynn

et al. 2002

Blood

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Our inability to purify hematopoietic stem cells (HSCs) precludes direct study of many aspects of their behavior in the clinical hematopoietic stem cell transplantation (HSCT) setting. We indirectly assessed stem/progenitor cell behavior in the first year after HSCT by examining changes in neutrophil telomere length, X-inactivation ratios, and cycling of marrow progenitors in 25 fully engrafted allogeneic HSCT recipients. Donors were sampled once and recipients at engraftment and 2 to 6 months and 12 months after HSCT. Telomere length was measured by an in-gel hybridization technique, X-inactivation ratios were measured by the human androgen receptor assay, and cell cycle status was determined by flow cytometric analysis of pyronin Y-and Hoechst 33342-stained CD34 ؉ CD90 ؉ and CD34 ؉ CD90 ؊ marrow cells. Compared with their donors, recipients' telomeres were shortened at engraftment (؊424 base pairs [bp]; P < .0001), 6 months (؊495 bp; P ‫؍‬ .0001) after HSCT, and 12 months after HSCT (؊565 bp; P < .0001). There was no consistent pattern of change in telomere length from 1 to 12 months after HSCT; marked, seemingly random, fluctuations were common. In 11 of 11 informative recipients, donor X-inactivation ratios were faithfully reproduced and maintained. The proportion of CD34 ؉ CD90 ؉ progenitors in S/G 2 /M was 4.3% in donors, 15.7% at 2 to 6 months (P < .0001) after HSCT, and 11.5% at 12 months after HSCT (P < .0001, versus donors; P ‫؍‬ .04, versus 2-6 months). Cycling of CD34 ؉ CD90 ؊ progenitors was largely unchanged. We infer that (1) HSCT-induced accelerated telomere loss is temporary and unlikely to promote graft failure or clonal hematopoietic disorders and (2)

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CD34+ cells from mobilized peripheral blood retain fetal bone marrow repopulating capacity within the Thy-1+ subset following cell division ex vivo

Cited by 27 publications

References 34 publications

Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

Stromal cells retard the differentiation of CD34+CD38low/neg human primitive progenitors exposed to cytokines independent of their mitotic history

Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss

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