Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure

Bartolucci, Jorge; Verdugo, Fernando; González, Paz L.; Larrea, Ricardo; E, Abarzúa; Goset, Carlos; Rojo, Pamela; Palma, Iván; Lamich, Rubén; Pedreros, Pablo; Valdivia, Gloria; Lopez, Valentina M.; Nazzal, Carolina; Alcayaga‐Miranda, Francisca; Cuenca, Jimena; Brobeck, Matthew; Patel, Amit N.; Figueroa, Fernando; Khoury, Maroun

doi:10.1161/circresaha.117.310712

Cited by 363 publications

(222 citation statements)

References 52 publications

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“…Although other studies have investigated the efficacy of cell‐based therapy in mixed patient populations of cardiomyopathy,24, 25, 26 this is the first study to directly compare clinical and phenotypic outcomes in response to MSCs delivered by TESI for the treatment of 2 different etiologies of cardiomyopathy, namely, DCM and ICM. Pooling the data from 3 single‐institution, phase I/II clinical trials demonstrates that TESI of MSCs provides clinical benefit in both ischemic and non‐ischemic LV dysfunction and HF.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, in a phase II dose‐escalation study investigating immunoselected allogeneic bone marrow–derived mesenchymal progenitor cells delivered by TESI in patients with ICM and DCM, no differences were observed in EF at 1 year of follow‐up, although the high‐dose group had a significant reduction in LV ESV and EDV, indicating improvement in reverse remodeling at 6 months and a nonsignificant decrease of both ESV and EDV at 12 months 24. More recently, the Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy showed that intravenously infused umbilical cord–derived MSCs produced significant improvements in EF, NYHA class, and MLHFQ at 3, 6, and 12 months of follow‐up in patients with HF attributable to either ischemic or nonischemic causes 25. The differences between these studies may be attributable, at least in part, to differences in the cell types studied and to the use of autologous versus allogeneic cells, underscoring the need to do further larger clinical studies.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Tompkins

Rieger²,

Florea³

et al. 2018

JAHA

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BackgroundIschemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done.Methods and ResultsWe conducted a subanalysis of 3 single‐center, randomized, and blinded clinical trials: (1) TAC‐HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON‐DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1‐year cardiac structure and function and quality‐of‐life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within‐group, P=0.002) compared to ICM (1.5%; within‐group, P=0.14; between‐group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (−0.2 mL; P=0.73; between‐group, P=0.02). End‐diastolic volume improved only in ICM (10.6 mL; P=0.04) and end‐systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (−0.04; P=0.0002). End‐diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (−4.1 g; P=0.34; between‐group, P=0.007). The 6‐minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between‐group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between‐group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (−19.5; P=0.002) and ICM (−6.4; P=0.03; δ between‐group difference P=0.042) patients.ConclusionsMesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: TAC‐HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON‐DCM: NCT01392625.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Tompkins

Rieger²,

Florea³

et al. 2018

JAHA

View full text Add to dashboard Cite

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“…In this issue of Circulation Research , the results of the RIMECARD study by Bertolucci et al 12 represent the first exploration in human subjects of the activity of umbilical cord-derived MSCs as potential heart failure therapy. This study enrolled patients with stable heart failure, reduced ejection fraction (<40%), and New York Heart Association heart failure classes I–III as a consequence of either stable ischemic or nonischemic cardiomyopathy; and excluded patients with end-stage heart failure, defined as American College of Cardiology Foundation/American Heart Association stage D candidates for cardiac transplantation or mechanical assistance.…”

Section: The Umbilical Cord Meets the Myocardiummentioning

confidence: 99%

“…While the exploration of UC-derived MSCs is novel in itself, an additionally important element of the Bertolucci et al 12 study is its reliance on intravenous delivery of the putatively therapeutic cells. In parallel with the Butler et al study earlier this year 3 , exploring intravenous delivery of BM-MSCs, early suggestions of physiological effect shown both clinically and by biomarkers in the Bertolucci study are particularly exciting.…”

Section: Broad Implications Of Intravenous Efficacymentioning

confidence: 99%

Cardiac Cell Therapy Evolving From Complex to Straightforward

March

Pepine

2017

Circulation Research

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“…HGF/c-Met signaling has emerged as an endogenous protective factor that maintains renal architecture and reconstructs a microenvironment under various physiologic and pathophysiologic conditions, whereas genetic ablation of c-Met in tubular or glomerular cells aggravated renal injuries [19,23,24]. MSCs of different origins are also described to be the sources of HGF [25,26], and coculture of MSCs with certain stromal cells promoted HGF synthesis in MSCs [19,27]. To date, there has been no report of HGF production in obese kidney treated with iPS-MSCs infusion, not to mention activation of HGF/c-Met signaling in the lipotoxic microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells via Hepatocyte Growth Factor/c-Met Signaling in Obesity-Associated Kidney Injury

Leung

Chan

et al. 2019

Stem Cells Translational Medicine

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Recent advances in the understanding of lipid metabolism suggest a critical role of endoplasmic reticulum (ER) stress in obesity‐induced kidney injury. Hepatocyte growth factor (HGF) is a pleiotropic cytokine frequently featured in stem cell therapy with distinct renotropic benefits. This study aims to define the potential link between human induced pluripotent stem cell‐derived mesenchymal stem cells (iPS‐MSCs)/bone marrow‐derived MSCs (BM‐MSCs) and ER stress in lipotoxic kidney injury induced by palmitic acid (PA) in renal tubular cells and by high‐fat diet (HFD) in mice. iPS‐MSCs or BM‐MSCs alleviated ER stress (by preventing induction of Bip , chop , and unfolded protein response), inflammation ( Il6 , Cxcl1 , and Cxcl2 ), and apoptosis ( Bax/Bcl2 and terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling‐positive cells) in renal cortex of animals exposed to HFD thus mitigating histologic damage and albuminuria, via activating HGF/c‐Met paracrine signaling that resulted in enhanced HGF secretion in the glomerular compartment and c‐Met expression in the tubules. Coculture experiments identified glomerular endothelial cells (GECs) to be the exclusive source of glomerular HGF when incubated with either iPS‐MSCs or BM‐MSCs in the presence of PA. Furthermore, both GEC‐derived HGF and exogenous recombinant HGF attenuated PA‐induced ER stress in cultured tubular cells, and this effect was abrogated by a neutralizing anti‐HGF antibody. Taken together, this study is the first to demonstrate that MSCs ameliorate lipotoxic kidney injury via a novel microenvironment‐dependent paracrine HGF/c‐Met signaling mechanism to suppress ER stress and its downstream pro‐inflammatory and pro‐apoptotic consequences. stem cells translational medicine 2019;8:898&910

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Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure

Cited by 363 publications

References 52 publications

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

Cardiac Cell Therapy Evolving From Complex to Straightforward

Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells via Hepatocyte Growth Factor/c-Met Signaling in Obesity-Associated Kidney Injury

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