Potential Strategies for Clinical Translation of Repeated Cell Therapy

Vrtovec, Bojan; Bolli, Roberto

doi:10.1161/circresaha.118.314653

Cited by 14 publications

(10 citation statements)

References 15 publications

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“…MSC infusions have been investigated as a treatment means for cardiac disease for more than a decade. Although accumulating evidence suggests that the MSC infusion can improve the cardiac function [ 34 ], however, information on the long-term dynamic outcomes of multiple hiPSC-MSC infusions on cardiac disease is unavailable.…”

Section: Discussionmentioning

confidence: 99%

Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model

Guo

Zhang

et al. 2020

BioMed Research International

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Mounting evidence indicates that the mesenchymal stem cell (MSC) injection is safe and efficacious for treating cardiomyopathy; however, there is limited information relating to multiple intravenous injections of human-induced pluripotent stem cell-derived mesenchymal stem cell (hiPSC-MSC) and long-term evaluation of the cardiac function. In the current study, MSC-like cells were derived from human-induced pluripotent stem cells through valproic acid (VPA) induction and continuous cell passages. The derived spindle-like cells expressed MSC-related markers, secreted angiogenic and immune-regulatory factors, and could be induced to experience chondrogenic and adipogenic differentiation. During the induction process, expression of epithelial-to-mesenchymal transition- (EMT-) related gene N-cadherin and vimentin was upregulated to a very high level, and the expression of pluripotency-related genes Sox2 and Oct4 was downregulated or remained unchanged, indicating that VPA initiated EMT by upregulating the expression of EMT promoting genes and downregulating that of pluripotency-related genes. Two and four intravenous hiPSC-MSC injections (106 cells/per injections) were provided, respectively, to model rats one week after acute myocardial infarction (AMI). Cardiac function parameters were dynamically monitored during a 12-week period. Two and four cell injections significantly the improved left ventricular ejection fraction and left ventricular fractional shortening; four-injection markedly stimulated angiogenesis reduced the scar size and cell apoptosis number in the scar area in comparison with that of the untreated control model rats. Although the difference was insignificant, the hiPSC-MSC administration delayed the increase of left ventricular end-diastolic dimension to different extents compared with that of the PBS-injection control. No perceptible immune reaction symptom or hiPSC-MSC-induced tumour formation was found over 12 weeks. Compared with the PBS-injection control, four injections produced better outcome than two injections; as a result, at least four rounds of MSC injections were suggested for AMI treatment.

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Section: Discussionmentioning

confidence: 99%

Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model

Guo

Zhang

et al. 2020

BioMed Research International

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“…After two decades of intensive research in the field of cell therapy for heart disease, conclusive demonstration of therapeutic efficacy of the cells is still lacking, and a fundamental understanding of how cell therapy works is still elusive[1, 3, 4, 29-31]. This has led to discussions of changes in the field and search for new paradigms for future research.…”

Section: Discussionmentioning

confidence: 99%

“…Despite two decades of intensive research in cell therapy for heart disease, the optimal cell type, dosage, delivery method and frequency are still elusive, as is the mechanism behind the observed cardiac benefits of cell therapy[1, 2]. The available evidence supports two fundamental concepts: i) the majority of cell-related effects do not result from direct cardiomyocyte differentiation but rather from paracrine mechanisms[3], ii) all cells, regardless of cell type or delivery approach, fail to engraft in the heart to a significant extent[4]. Therefore, expecting a single administration of short-lasting cells to produce long-term benefits may be unrealistic.…”

Section: Introductionmentioning

confidence: 99%

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Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice

Nong

Guo

Tomlin

et al. 2020

Preprint

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21Background: In the field of cell therapy for heart disease, a new paradigm of repeated 22 dosing of cells has recently emerged. However, the lack of a repeatable cell delivery 23 method in preclinical studies in rodents is a major obstacle to investigating this 24 paradigm. 25 Methods and Results:We have established and standardized a method of 26 echocardiography-guided percutaneous left ventricular intracavitary injection (echo-27 guided LV injection) as a cell delivery approach in infarcted mice. Here, we describe the 28 method in detail and address several important issues regarding it. First, by integrating 29 anatomical and echocardiographic considerations, we have established strategies to 30 determine a safe anatomical window for injection in infarcted mice. Second, we 31 summarize our experience with this method (734 injections). The overall survival rate 32 was 91.4%. Previous studies results suggest that 1×10 6 cells delivered via this method 33 yielded similar retention in the heart at 24 h as 1×10 5 cells delivered via intracoronary or 34 intramyocardial injection. Lastly, we examined the efficacy of this cell delivery approach. 35Compared with vehicle treatment, cardiac mesenchymal cells (CMCs) delivered via this 36 method improved cardiac function assessed both echocardiographically and 37 hemodynamically. Furthermore, repeated injections of CMCs via this method yielded 38 greater cardiac function improvement than single dose administration. 39 Conclusion: Echo-guided LV injection is a feasible, reproducible, relatively less 40 invasive and effective delivery method for cell therapy in heart disease. It is an 41 important approach that could move the field of cell therapy forward, especially with 42 regard to repeated cell administrations. 43 44 Introduction 45 Despite two decades of intensive research in cell therapy for heart disease, the optimal 46 cell type, dosage, delivery method and frequency are still elusive, as is the mechanism 47 behind the observed cardiac benefits of cell therapy[1, 2]. The available evidence 48 supports two fundamental concepts: i) the majority of cell-related effects do not result 49 from direct cardiomyocyte differentiation but rather from paracrine mechanisms[3], ii) all 50 cells, regardless of cell type or delivery approach, fail to engraft in the heart to a 51 significant extent[4]. Therefore, expecting a single administration of short-lasting cells to 52 produce long-term benefits may be unrealistic. A paradigm shift from single 53 administration to repeated administrations of cells is underway[1, 3-5]. 54 Typical cell delivery approaches in clinical studies include intracoronary infusion, 55 transendocardial injection, and direct epicardial injection[1, 2]. The first two are catheter-56 based, and can be repeated without opening the chest although it would be practically 57 difficult to perform repeated catheter-based deliveries in humans. However, in 58 preclinical studies in rodents, repeated cell administrations can be difficult to perform. 59 Most cell...

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“…Consistently, in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial, administration of a higher percentage of CD45 + CD31 low bone marrow-derived single cells resulted in significantly reduced infarct size at 6 months after cell therapy. 11 Recently, several studies have reported that repeated injections of bone marrow-derived cells significantly improve LV function and long-term survival 12,13.…”

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confidence: 99%

Insights From 10-Year Outcomes of Mesenchymal Stem Cell Transplantation in Heart Failure Patients

Inoue

Takamura

2019

Circ J

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cardiac function in rodents. 2 Since the mid-2000 s, clinical trials, including randomized controlled trials (RCTs), using bone marrow-derived MSCs (BMMSCs) have been conducted. 3 A meta-analysis of cell therapy studies using bone marrow-derived cells, including BMMSCs (50 studies, 2,625 recipients) demonstrated that patients receiving cell therapy resulted in improvement of LV function with greater EF (+3.96%), reduced infarct size, and smaller LV volume. 4

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Potential Strategies for Clinical Translation of Repeated Cell Therapy

Cited by 14 publications

References 15 publications

Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model

Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model

Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice

Insights From 10-Year Outcomes of Mesenchymal Stem Cell Transplantation in Heart Failure Patients

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