Inhibition of Let-7 Processing in Adult Murine Hematopoietic Stem Cells Induces a Fetal-Like High Self-Renewal Pattern in Their Progeny
Bibliographic record
Abstract
Abstract Abstract 45 Fetal hematopoietic stem cells (HSCs) in mice differ from their adult counterparts in a number of key properties. These include a higher cycling activity, an ability to more rapidly reconstitute the HSC compartment of irradiated recipient mice, a higher output of myeloid as compared to lymphoid progeny, and a greater sensitivity to the self-renewal promoting activity of Steel factor. We have previously shown that most of these features of fetal HSCs are sustained until 3 weeks after birth at which time they are rapidly (within 1 week), completely and permanently replaced with the corresponding properties of adult HSCs. A candidate regulator of this transition, Hmga2, was identified based on its greater expression in highly purified fetal versus adult HSCs (CD45+EPCR+CD48−CD150+; E-SLAM cells) with persistence of this difference in the matching lineage-negative (lin−) compartments. Experiments in which Hmga2 was overexpressed by lentiviral transduction of purified adult HSCs which were then transplanted into irradiated mice provided evidence that this chromatin remodeling factor can activate a fetal-like HSC program in these cells; i.e., more rapidly reconstitute the HSC compartment (increased self-renewal response) and produce clones with a higher proportion of myeloid cells. Based on the known ability of the let-7 family of microRNAs (miRNAs) to target Hmga2 transcripts resulting in their degradation and/or translational repression, we next hypothesized that let-7 miRNAs might be involved in controlling HSC developmental programs. A comparison of the levels of expression of 6 members of the let-7 family in purified fetal and adult HSCs, as well as in lin− hematopoietic cells, showed that transcripts for all of these are higher in the adult subsets, although this difference was significant only for let-7b (p<0.05). Since Lin28 is a natural inhibitor of let-7 miRNA biogenesis we proposed that overexpression of this protein might be used to simultaneously inhibit all let-7 miRNA species and therefore modulate let-7-mediated effects in HSCs. Transduction of BA/F3 cells with a Lin28-YFP lentiviral vector led to an elevated expression of Lin28 and a significant decrease in multiple let-7 miRNAs. To investigate the influence of Lin28 overexpression on adult HSC self-renewal activity in vivo, we used the same Lin28 lentiviral vector (or a control YFP vector) to transduce highly purified HSCs (40 E-SLAM cells, i.e. ∼20 HSCs/group/experiment, 3 experiments) in a 3–4-hour exposure protocol and then transplanted all of the cells directly into irradiated mice (total of 3–4 mice/group). The number of HSCs regenerated 6 weeks later was subsequently measured by performing limiting-dilution transplants in secondary mice (total of 12–16 secondary mice/group/experiment). Interestingly, analysis of the secondary recipients showed that the Lin28-overexpressing adult HSCs had expanded in the primary recipients ∼6-fold more than the control-virus transduced HSCs (p<0.001). These findings support our thesis that alterations in let-7 miRNA levels play a key role in regulating the developmental switch from fetal to adult HSCs programs that occurs between 3 and 4 weeks after birth in mice. Disclosures: No relevant conflicts of interest to declare.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
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".