Abstract 256: Paracrine miRNA-Crosstalk Between Human CD34+ Stem Cells and Selective Myocardial Cells Via Therapeutic Exosomes Promotes Repair of the Ischemic Heart
Bibliographic record
Abstract
Introduction: Earlier, in a first study of its kind, we have demonstrated a novel mechanism that therapeutically significant human CD34+ stem cells secrete membrane bound nano-vesicles called exosomes (CD34Exo). CD34Exo are angiogenic and constitute a critical component of the pro-angiogenic paracrine activity of the cells. Further, when transplanted locally, cell-free CD34Exo induce ischemic tissue repair in a murine hindlimb ischemia model. Here, we hypothesize that exosomes released via paracrine secretion from human CD34+ cells mediate myocardial repair by direct transfer of microRNAs to target cells in the heart. Methods and Results: When injected into mouse ischemic myocardium, cell-free CD34Exo replicated the therapeutic activity of human CD34+ cells by significantly improving ischemia (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis, 27±2 v 48±7%; p<0.05, n=7-12) compared with PBS control. Interestingly, confocal imaging and flow cytometry analyses of the exosomes-injected ischemic myocardial tissue revealed that CD34Exo was selectively internalized into endothelial cells and cardiomyocytes. CD34Exo, which is enriched with miR126, induced the expression of miR126 and several pro-angiogenic mRNAs in the exosomes-treated ischemic myocardium, but did not affect the endogenous synthesis of miR126. CD34Exo lacking miR126 had decreased angiogenic activity in vitro and decreased proangiogenic gene expression in vivo indicating that miR126 is important for CD34Exo function. Imaging using fluorescent miR126 confirms that CD34Exo directly transferred miR126 and possibly other yet to be identified moieties from its cargo, selectively to endothelial cells and cardiomyocytes in the ischemic heart. Conclusion: Our results reveal a novel molecular and trafficking mechanism of CD34Exo that may be responsible for intercellular transfer of genetic information such as miRNAs from human CD34+ stem cells, selectively to endothelial cells and cardiomyocytes inducing changes in gene expression, angiogenesis and myocardial recovery. Exosomes-shuttled miRNAs may signify amplification of stem cell function and may explain the therapeutic benefits associated with human CD34+ cell therapy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".