Dichotomous Regulation of Lysosomes By MYC and Tfeb Controls Hematopoietic Stem Cell Fate
Bibliographic record
Abstract
Human long-term hematopoietic stem cells (LT-HSC) residing at the top of the hematopoietic hierarchy must meet enormous daily demand (~10e11 cells daily) while also sustaining life-long maintenance of the stem cell pool through self-renewal. This hierarchical organization is widely thought to protect LT-HSC from exhaustion by maintaining them in a quiescent and undifferentiated state, activating only in response to microenvironment signals to generate highly proliferative but more short-lived populations including short-term HSC (ST-HSC) and committed progenitors. When called upon to exit this dormant state, HSC must respond and adapt their metabolism and nutrient uptake to meet increased bioenergetic demands for cell growth and differentiation. At the same time, the events underlying cellular and metabolic activation must also be suppressed to allow LT-HSC to re-enter quiescence and ultimately maintain the LT-HSC pool through self-renewal. Thus, proper sensing of cellular output demands must be coordinated with the cell cycle and metabolic machinery of LT-HSC to balance stem cell fates and maintain hematopoietic homeostasis. However, the regulatory circuits of this demand-adapted regulation of early hematopoiesis are largely unknown. The ability of cells to receive signals or take up nutrients depends on proteins that are embedded within the plasma membrane. These proteins move to the cell's interior through endocytosis and can be degraded in the lysosomes or rerouted back to the cell surface and reused. Moreover, lysosomes are the terminal catabolic stations of the autophagy pathway that is essential for preserving stem cell function through clearance of toxic cellular components. However, little is known about the regulation and role of lysosomes in the stem cell context. Here, we describe the unexpected finding that lysosomes, whose activity is intricately balanced by TFEB and MYC, are instrumental for regulating the stemness and differentiation properties of human LT-HSC. Furthermore, we found that TFEB, which is normally implicated in stress response, induces a constitutive lysosomal flux in unperturbed LT-HSC that actively maintains quiescence, preserves self-renewal and governs lineage commitment. These effects are accompanied by endolysosomal degradation of membrane receptors, such as the transferrin receptor 1 (TfR1), pointing to a role for TFEB in coordinating how LT-HSC sense environmental changes and initiate the earliest steps of their fate transitions and lineage commitment decisions. These transitions are regulated by a TFEB/MYC dichotomy where MYC is a driver of LT-HSC anabolism and activation and counteracts TFEB function by serving as a negative transcriptional regulator of lysosomes. Moreover, our findings further suggest that active suppression of TFEB and its downstream lysosomal degradation of TfR1 within LT-HSC is required for commitment along the erythroid lineage: activation of TFEB can abolish erythroid differentiation even after lineage commitment has occurred. In summary, we uncovered a MYC-TFEB-mediated dichotomous regulation of lysosomal activity that is required to balance anabolic and catabolic processes that ultimately impact human LT-HSC fate determination. Figure Disclosures Takayanagi: Kirin Holdings Company, Ltd: Current Employment. Dick:Bristol-Myers Squibb/Celgene: Research Funding.
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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 | 0.001 | 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".