c-Myb Dependent Smooth Muscle Cell Differentiation from Mouse Embryonic Stem Cells
Bibliographic record
Abstract
Vascular smooth muscle cells (VSMC) serve as key constituents of the developing vasculature, ensuring stability of the nascent vessels, and are essential for the proper performance of the mature cardiovascular system. Pathological alterations in SMC biology, manifesting as perturbations in the differentiation state of SMC, play a pivotal role in the development and progression of various vascular diseases. Thus an understanding of the mechanisms and factors that control SMC differentiation underlies the potential for diagnostic and therapeutic advances. As such, this thesis aimed to implicate the c-Myb transcription factor in the process of SMC differentiation. For this purpose, in vitro assays were developed using the embryoid body (EB) model system, suitable for clarifying the molecular pathways and extrinsic factors that promote or obstruct SMC lineage specification and maturation to the contractile phenotype.\nContractile activity was observed in the developing EBs, and further characterized as smooth muscle and cardiac contractions. Temporal induction of SM-specific markers preceded and paralleled contractile SMC appearance and their mRNA levels predicted the relative ability of distinct mouse ES cell (mESC) lines to generate EBs with contracting SMC. Using fluorescent SM-specific promoter-reporter gene strategy it was shown that spontaneous SM-contractions coincide with SM-myosin-heavy-chain (SM-MHC) promoter activity. Moreover, this technology was employed to generate SMC (SM-MHC+) in a scalable stirred-suspension culture system. \nThis thesis addressed the effects of c-myb ablation on SMC differentiation both in vitro and in vivo. c-myb-/- mESC were unable to produce EBs with spontaneously contracting SMC, but gave rise to contracting cardiomyocytes unimpaired. Temporal patterns of myogenic and SM-specific gene expression levels during the course of differentiation revealed that, unlike wild-type EBs, c-myb-/- EBs lacked robust induction of these critical markers. Accordingly, c-myb-/- EBs exhibited significantly reduced SMC numbers. Additionally, in chimaeric EB model substantial contribution by c-myb-/- mESC was detrimental to the development of SM-contractions. To corroborate the in vitro data, chimaeric embryos and adult mice were used to demonstrate significantly reduced c-myb-/- cell contribution to vascular and visceral SMC lineages in vivo. \nCollectively, this thesis assigns a novel role for the c-Myb transcription factor and advances knowledge of in vitro SMC differentiation.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".