Transplanted CD34+ Cells Stimulated with Flt3 Ligand and Granulocyte-Colony Stimulating Factor Display An Impaired Early Reconstitution Capacity
Bibliographic record
Abstract
Abstract Flt3/flk2 belongs to the class III hematopoietic growth factor receptors with intrinsic kinase activity, ligand-activated tyrosine phosphorylation and a central role in early stages of hematopoiesis. Flt3-ligand (FL) has been shown to enhance the effects of several growth factors, including Granulocyte-colony stimulating factor (G-CSF). In this study the reconstitution ability of FL+G-CSF primed CD34+ cells was evaluated in a nonhuman primate model of radiation-induced myeloablative treatment followed by transplantation of stimulated autologous bone marrow (BM) and/or peripheral blood (PB) cells. Rhesus monkeys (n=9) were subjected to subcutaneous injections with FL (100 μg/kg/day) and G-CSF (100 μg/kg/day) for 7 to 14 days and subsequently irradiated with a lethal dose of total body irradiation (TBI) followed by transplantation with primed stem cells or with a midlethal dose of TBI (n=2) without transplantation. White blood cell counts (WBC) in PB showed a steep increase and reached a mean level of 98.9×109/L (71.5–131.7×109/L) after 7 days (P<0.01). BM cellularity increased from 35.2×109/L before treatment to 193.8×109/L after priming (95.0–348.2×109/L) (P<0.01). CD34+ cells displayed a 1-log increase (P<0.01) in BM and a 2-log increase in PB (P<0.01). Both total nucleated and CD34+ cell numbers reached after 7 days a steady state level, which was maintained until cessation of growth factor treatment. Treatment with FL+G-CSF resulted in a moderate increase (2-fold) of CFU-GM in BM after 7 days (P<0.05) but did not affect BFU-E, consistent with the predilection of FL for myeloid and lymphoid cells, in contrast to SCF, which predominantly influences the erythroid and thrombopoietic lineage. The effect of treatment with FL+G-CSF on WBC was significantly greater than treatment with either G-CSF at day 7 (P<0.05) or FL at day 7 and 14 (P<0.01). Lethally irradiated monkeys, transplanted with FL+G-CSF stimulated cells displayed a much slower regeneration of WBC, platelets and reticulocytes relative to the cell number transplanted and were consequently in need of prolonged antimicrobial prophylaxis and transfusions. Furthermore, these monkeys displayed regeneration patterns consistent with a 1-log depletion of repopulating cells relative to non-stimulated BM cells. Mid-lethal irradiated FL+G-CSF treated monkeys were not transplanted to study the intrinsic regeneration capacity of primed BM. These monkeys displayed normal regeneration of reticulocytes, platelets and WBC. Thus, stimulation with FL+G-CSF leads to a steep and synergistic increase of nucleated and CD34+ cells in both BM and PB. Priming with FL+G-CSF does not affect the intrinsic regeneration capacity of BM after radiation; but when transplanted, primed CD34+ cells do not per se contribute to accelerated short-term engraftment after transplantation, rather the reconstitution patterns were consistent with on average one order of magnitude stem cell depletion relative to the numbers of CD34+ cells transplanted.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".