Calcium‐dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow‐derived mesenchymal stem cells
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».