Calcium‐dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow‐derived mesenchymal stem cells
Bibliographic record
Abstract
Key points Ex vivo proliferated c‐Kit + endogenous cardiac progenitor cells (eCPCs) obtained from mouse and human cardiac tissues have been reported to express a wide range of functional ion channels. In contrast to previous reports in cultured c‐Kit + eCPCs, we found that ion currents were minimal in freshly isolated cells. However, inclusion of free Ca 2+ intracellularly revealed a prominent inwardly rectifying current identified as the intermediate conductance Ca 2+ ‐activated K + current (KCa3.1) Electrical function of both c‐Kit + eCPCs and bone marrow‐derived mesenchymal stem cells is critically governed by KCa3.1 calcium‐dependent potassium channels. Ca 2+ ‐induced increases in KCa3.1 conductance are necessary to optimize membrane potential during Ca 2+ entry. Membrane hyperpolarization due to KCa3.1 activation maintains the driving force for Ca 2+ entry that activates stem cell proliferation. Cardiac disease downregulates KCa3.1 channels in resident cardiac progenitor cells. Alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine. Abstract Endogenous c‐Kit + cardiac progenitor cells (eCPCs) and bone marrow (BM)‐derived mesenchymal stem cells (MSCs) are being developed for cardiac regenerative therapy, but a better understanding of their physiology is needed. Here, we addressed the unknown functional role of ion channels in freshly isolated eCPCs and expanded BM‐MSCs using patch‐clamp, microfluorometry and confocal microscopy. Isolated c‐Kit + eCPCs were purified from dog hearts by immunomagnetic selection. Ion currents were barely detectable in freshly isolated c‐Kit + eCPCs with buffering of intracellular calcium (Ca 2+ i ). Under conditions allowing free intracellular Ca 2+ , freshly isolated c‐Kit + eCPCs and ex vivo proliferated BM‐MSCs showed prominent voltage‐independent conductances that were sensitive to intermediate‐conductance K + ‐channel (KCa3.1 current, I KCa3.1 ) blockers and corresponding gene ( KCNN4 )‐expression knockdown. Depletion of Ca 2+ i induced membrane‐potential ( V mem ) depolarization, while store‐operated Ca 2+ entry (SOCE) hyperpolarized V mem in both cell types. The hyperpolarizing SOCE effect was substantially reduced by I KCa3.1 or SOCE blockade (TRAM‐34, 2‐APB), and I KCa3.1 blockade (TRAM‐34) or KCNN4 ‐knockdown decreased the Ca 2+ entry resulting from SOCE. I KCa3.1 suppression reduced c‐Kit + eCPC and BM‐MSC proliferation, while significantly altering the profile of cyclin expression. I KCa3.1 was reduced in c‐Kit + eCPCs isolated from dogs with congestive heart failure (CHF), along with corresponding KCNN4 mRNA. Under perforated‐patch conditions to maintain physiological [Ca 2+ ] i , c‐Kit + eCPCs from CHF dogs had less negative resting membrane potentials (−58 ± 7 mV) versus c‐Kit + eCPCs from control dogs (−73 ± 3 mV, P < 0.05), along with slower proliferation. Our study suggests that Ca 2+ ‐induced increases in I KCa3.1 are necessary to optimize membrane potential during the Ca 2+ entry that activates progenitor cell proliferation, and that alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine.
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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) | 0.001 | 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".