Cell therapy for cardiac repair: what is needed to move forward?

Bolli, Roberto; Ghafghazi, Shahab

doi:10.1038/nrcardio.2017.38

Cited by 35 publications

(42 citation statements)

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“…Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have the dual promise of being used for cell-based therapies to combat cardiac diseases [1–3] and as a model for cardiac cell development. For these cell-based therapies to be successful, it is imperative that the transplanted cells integrate with the host cells to improve cardiac function.…”

Section: Introductionmentioning

confidence: 99%

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

et al. 2018

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Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are at the center of new cell-based therapies for cardiac disease, but may also serve as a useful in vitro model for cardiac cell development. An intriguing feature of hESC-CMs is that although they express contractile proteins and have sarcomeres, they do not develop transverse-tubules (T-tubules) with adult-like Ca2+ release units (CRUs). We tested the hypothesis that expression of the protein BIN1 in hESC-CMs promotes T-tubules formation, facilitates CaV1.2 channel clustering along the tubules, and results in the development of stable CRUs. Using electrophysiology, [Ca2+]i imaging, and super resolution microscopy, we found that BIN1 expression induced T-tubule development in hESC-CMs, while increasing differentiation towards a more ventricular-like phenotype. Voltage-gated CaV1.2 channels clustered along the surface sarcolemma and T-tubules of hESC-CM. The length and width of the T-tubules as well as the expression and size of CaV1.2 clusters grew, as BIN1 expression increased and cells matured. BIN1 expression increased CaV1.2 channel activity and the probability of coupled gating within channel clusters. Interestingly, BIN1 clusters also served as sites for sarcoplasmic reticulum (SR) anchoring and stabilization. Accordingly, BIN1-expressing cells had more CaV1.2-ryanodine receptor junctions than control cells. This was associated with larger [Ca2+]i transients during excitation-contraction coupling. Our data support the view that BIN1 is a key regulator of T-tubule formation and CaV1.2 channel delivery. By studying the role of BIN1 during the differentiation of hESC-CMs, we show that BIN1 is also important for CaV1.2 channel clustering, junctional SR organization, and the establishment of EC coupling.

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Section: Introductionmentioning

confidence: 99%

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

et al. 2018

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“…It is becoming increasingly apparent that poor engraftment of transplanted cells and their rapid clearance from the host myocardium are major factors limiting the therapeutic efficacy of virtually all cell types tested thus far, and may contribute to the small or undetectable beneficial effects observed in clinical trials 1, 2. We have recently shown that repeated cell administrations can partially overcome the failure of cells to engraft and significantly enhance their salubrious actions by augmenting the exposure of diseased myocardium to transplanted cells.…”

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confidence: 99%

“…We have recently shown that repeated cell administrations can partially overcome the failure of cells to engraft and significantly enhance their salubrious actions by augmenting the exposure of diseased myocardium to transplanted cells. Specifically, we have found that, in the setting of ischemic cardiomyopathy, 3 doses of cells, given a few weeks apart, result in greater improvement in left ventricular (LV) function than a single dose; this was observed in 2 different species (mice and rats) and with 2 different cell types (c‐kit POS cardiac progenitor cells [CPCs]3 and cardiac mesenchymal cells4), suggesting that the superiority of multiple doses is not dependent on species or cell type 1, 2. These results support the concept that the use of multiple doses is an important strategy to augment the efficacy of cell therapy.…”

mentioning

confidence: 99%

“…The mechanism for the greater efficacy of repeated cell administrations remains unclear, but likely involves a higher average density of transplanted cells over time 1, 2. The myocardial content of transplanted cells declines rapidly after injection 5, 6.…”

mentioning

confidence: 99%

“…The myocardial content of transplanted cells declines rapidly after injection 5, 6. In the setting of multiple doses, each injection results in a transient spike in the number of transplanted cells in the tissue, such that the average density of these cells over time is higher than after a single injection; this situation prolongs the exposure of the host tissue to the paracrine actions of the cells 1, 2. However, it remains possible that a similar effect could be achieved simply by increasing the number of cells administered in 1 injection.…”

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confidence: 99%

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Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

Tang

Nakamura

et al. 2018

JAHA

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BackgroundWe have recently found that 3 repeated doses (12×106 each) of c‐kitPOS cardiac progenitor cells (CPCs) were markedly more effective than a single dose of 12×106 cells in alleviating postinfarction left ventricular dysfunction and remodeling. However, since the single‐dose group received only one third of the total number of CPCs given to the multiple‐dose group, it is unknown whether the superior therapeutic efficacy was caused by repeated treatments per se or by administration of a higher total number of CPCs. This issue has major clinical implications because multiple cell injections in patients pose significant challenges, which would be obviated by using 1 large injection. Accordingly, we determined whether the beneficial effects of 3 repeated CPC doses can be recapitulated by 1 large dose containing the same total number of cells.Methods and ResultsRats with a 30‐day‐old myocardial infarction received 3 echo‐guided intraventricular infusions, 35 days apart, of vehicle‐vehicle‐vehicle, 36×106 CPCs‐vehicle‐vehicle, or 3 equal doses of 12×106 CPCs. Infusion of a single, large dose of CPCs (36×106 cells) produced an initial improvement in left ventricular function, but no further improvement was observed after the second and third infusions (both vehicle). In contrast, each of the 3 doses of CPCs (12×106) caused a progressive improvement in left ventricular function, the cumulative magnitude of which was greater than with a single dose. Unlike the single dose, repeated doses reduced collagen content and immune cell infiltration.ConclusionsThree repeated doses of CPCs are superior to 1 dose even though the total number of cells infused is the same, possibly because of greater antifibrotic and anti‐inflammatory actions.

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Platelet‐Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury

Huang

et al. 2018

Adv Funct Materials

106

112

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Cardiovascular disease is the leading cause of mortality in the world. While reperfusion therapy is vital for patient survival post-heart attack, it also causes further tissue injury, known as myocardial ischemia/reperfusion (I/R) injury in clinical practice. Exploring ways to attenuate I/R injury is of clinical interest for improving post-ischemic recovery. A platelet-inspired nano-cell (PINC) that incorporates both prostaglandin E2 (PGE 2 )-modified platelet membrane and cardiac stromal cellsecreted factors to target the heart after I/R injury is introduced. By taking advantage of the natural infarct-homing ability of platelet membrane and the overexpression of PGE 2 receptors (EPs) in the pathological cardiac microenvironment after I/R injury, the PINCs can achieve targeted delivery of therapeutic payload to the injured heart. Furthermore, a synergistic treatment efficacy can be This article is protected by copyright. All rights reserved. 3 achieved by PINC, which combines the paracrine mechanism of stem cell therapy with the PGE 2 /EP receptor signaling that is involved in the repair and regeneration of multiple tissues. In a mouse model of myocardial I/R injury, intravenous injection of PINCs results in augmented cardiac function and mitigated heart remodeling, which is accompanied by the increase in cycling cardiomyocytes, activation of endogenous stem/progenitor cells, and promotion of angiogenesis. This approach represents a promising therapeutic delivery platform for treating I/R injury.

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Cell therapy for cardiac repair: what is needed to move forward?

Cited by 35 publications

References 10 publications

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes

Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

Platelet‐Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury

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