Sirtuin1 Regulates the Stem Cell Therapeutic Effects on Regenerative Capability for Treating Severe Heart Failure in a Juvenile Animal Model

Background: Transplantation of autologous somatic tissue-derived cells into the heart has been shown to yield functional recovery of the failing heart via “paracrine effects” that enhance the native regenerative process. We have introduced skeletal stem cell (SSC) sheet methods for treating severe heart failure (HF), in which scaffold-free cell-sheets are attached on the epicardial surface to maximize the paracrine effects. We herein report feasibility, safety and efficacy of SSC sheet transplantation for treating advanced HF. Methods: This study enrolled 27 patients (mean age, 51±15 years, DCM in 15 patients and ICM in 12 patients) with chronic advanced HF despite optimum treatments. Scaffold-free cell-sheets containing SSC (average: 3.5±1.9х108 cells) was transplanted over the left ventricular (LV) free wall via the left thoracotomy. Average follow-up was 2.5 (0.6-5.1) years. Results: All patients discharged from the hospital without procedure-related complications. Re-In-hospital treatment for congestive HF was required in 8 patients, who we defined as non-responder (Group N: n=8), while the other patients who were free from in-hospital cardiac treatments were defined as responder (Group R: n=19). The Group R exhibited decreased NYHA functional class (2.8±0.6 to 1.6±1.1 p<0.05) and increased 6-minute walk test (444±110 to 499±114m p<0.05) at 6 months, while these values maintained until the latest follow-up. Echocardiographically, LV systolic and diastolic diameters significantly decreased and ejection fraction significantly increased. In addition, both LV end-systolic and diastolic wall stress, assessed by cardiac CT scanning, significantly decreased (systolic: 377±76 to 317±88, diastolic: 116±98 to 51±32 kdynes/cm2, p<0.05 respectively) in the Group R. Multivariate analysis showed that preoperative duration of HF was a single independent risk factor for Group N with its hazard ratio 1.8 (p<0.05). Three-year freedom from cardiac death was 92%, while that from recurrence of HF was 70%. Conclusions: SSC sheet transplantation was feasible and safe in advanced HF patients. Functional recovery, including reduced LV wall stress, was gained in the selected patients, who received this treatment in early stage of advanced HF.

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Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report: Figure 1

European Heart Journal ◽

10.1093/eurheartj/ehv189 ◽

2015 ◽

Vol 36 (30) ◽

pp. 2011-2017 ◽

Cited By ~ 264

Author(s):

Philippe Menasché ◽

Valérie Vanneaux ◽

Albert Hagège ◽

Alain Bel ◽

Bernard Cholley ◽

...

Keyword(s):

Heart Failure ◽

Stem Cell ◽

Case Report ◽

Human Embryonic Stem Cell ◽

Clinical Case ◽

Embryonic Stem ◽

Severe Heart Failure ◽

Heart Failure Treatment ◽

Cardiac Progenitors ◽

Failure Treatment

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Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer’s Disease Animal Model

Stem Cells International ◽

10.1155/2021/5548630 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

HyeJu Jeong ◽

Ok Joon Kim ◽

Seung-Hun Oh ◽

Sanghoon Lee ◽

Han A. Reum Lee ◽

...

Keyword(s):

Stem Cells ◽

Animal Model ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Animal Models ◽

Umbilical Cord ◽

Extracellular Vesicles ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Significant Difference

Alzheimer’s disease (AD) animal studies have reported that mesenchymal stem cells (MSCs) have therapeutic effects; however, clinical trial results are controversial. Neprilysin (NEP) is the main cleavage enzyme of β-amyloid (Aβ), which plays a major role in the pathology and etiology of AD. We evaluated whether transplantation of MSCs with NEP gene modification enhances the therapeutic effects in an AD animal model and then investigated these pathomechanisms. We manufactured NEP gene-enhanced human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and intravenously transplanted them in Aβ1-42-injected AD animal models. We compared the differences in behavioral tests and immunohistochemical assays between four groups: normal, Aβ1-42 injection, naïve hUC-MSCs, and NEP-enhanced hUC-MSCs. Both naïve and NEP-enhanced hUC-MSC groups showed significant improvements in memory compared to the Aβ1-42 injection group. There was no significant difference between naïve and NEP-enhanced hUC-MSC groups. There was a significant decrease in Congo red, BACE-1, GFAP, and Iba-1 and a significant increase in BDNF, NeuN, and NEP in both hUC-MSC groups compared to the Aβ1-42 injection group. Among them, BDNF, NeuN, GFAP, Iba-1, and NEP showed more significant changes in the NEP-enhanced hUC-MSC group than in the naïve group. After stem cell injection, stem cells were not found. Extracellular vesicles (EVs) were equally observed in the hippocampus in the naïve and NEP-enhanced hUC-MSC groups. However, the EVs of NEP-enhanced hUC-MSCs contained higher amounts of NEP as compared to the EVs of naïve hUC-MSCs. Thus, hUC-MSCs affect AD animal models through stem cell-released EVs. Although there was no significant difference in cognitive function between the hUC-MSC groups, NEP-enhanced hUC-MSCs had superior neurogenesis and anti-inflammation properties compared to naïve hUC-MSCs due to increased NEP in the hippocampus by enriched NEP-possessing EVs. NEP gene-modified MSCs that release an increased amount of NEP within EVs may be a promising therapeutic option in AD treatment.

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Cortical Bone Stem Cell-Derived Exosomes' Therapeutic Effect On Myocardial Ischemia Reperfusion and Cardiac Remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00197.2021 ◽

2021 ◽

Author(s):

Giana J Schena ◽

Emma K. Murray ◽

Alycia N. Hildebrand ◽

Alaina L. Headrick ◽

Yijun Yang ◽

...

Keyword(s):

Heart Failure ◽

Stem Cell ◽

Cortical Bone ◽

Cardiac Remodeling ◽

Cardiac Fibroblasts ◽

Ischemia Reperfusion ◽

The United States ◽

Therapeutic Effects ◽

Murine Embryonic Fibroblast ◽

Fibroblast Migration

Heart failure is the one of the leading causes of death in the United States. Myocardial infarction (MI) is followed by cardiac remodeling involving extensive fibrosis and which can ultimately progress into heart failure. Previous studies have shown both that both post-MI and post-ischemia reperfusion (I/R), there is a reduction in scar size and improved cardiac function as a result of administration of cortical bone stem cell (CBSC) treatment. We investigated the effects of mouse CBSCs (mCBSC), human CBSCs (hCBSC), mCBSC-derived exosomes and hCBSC-derived exosomes on murine embryonic fibroblast (MEF) migration. Exosome depletion from the CBSC-CM enhanced the reduction in fibroblast migration, implying exosome contents are involved in fibroblast migration. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with TGFβ to activate fibrotic signaling before treatment with mCBSC- and hCBSC-derived exosomes. hCBSC-derived exosomes caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-derived exosome treatment. The group treated with both TGFβ and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability. A 24hr I/R study on mice showed that injection of mCBSCs and mCBSC-derived exosomes into the ischemic region of an infarct had a protective effect against I/R injury. Additionally, we found that mCBSC-derived exosomes recapitulate the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's therapeutic effects.

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Periodic whole body acceleration: A novel therapy for cardiovascular disease

VASA ◽

10.1024/0301-1526.36.4.261 ◽

2007 ◽

Vol 36 (4) ◽

pp. 261-266 ◽

Cited By ~ 11

Author(s):

Kohler ◽

Amann-Vesti ◽

Clarenbach ◽

Brack ◽

Noll ◽

...

Keyword(s):

Quality Of Life ◽

Heart Failure ◽

Endothelial Function ◽

Severe Heart Failure ◽

Walking Distance ◽

Whole Body ◽

Therapeutic Effects ◽

Motion Platform ◽

Body Acceleration

Background: Periodic whole body acceleration in the spinal axis (pGz) applied by a motion platform is a novel treatment modality that induced endothelial nitric oxide release into the circulation of animals, healthy subjects and patients with inflammatory diseases during single treatment sessions in previous studies. We hypothesized that patients with advanced arteriosclerotic diseases who are not candidates for a surgical intervention would clinically benefit from repeated pGz treatments over several weeks through improvement of endothelial function. Patients and methods: 11 patients, 5 men (37 to 71y) with stable ischemic heart disease, LVEF < 35%, NYHA stage > II, and 6 patients (51 to 83y, 1 woman) with intermittent leg claudication, Fontaine stage II, were enrolled after optimization of pharmacological therapy. PGz was applied for 40 min, 5 days/week during 5 weeks. Quality of life (SF-36 questionnaire), exercise performance, and endothelial function were assessed at baseline, during the treatment period, and 4 weeks after discontinuation of pGz. Results: PGz was well tolerated. In heart failure paitents, pGz therapy improved quality of life, increased 6 min walking distance by a mean ± SE of 105 ± 24 m, and improved postischemic skin hyperemia (p < .05 in all instances). In 4 of 6 patients with intermittent claudication, quality of life, treadmill walking distance and post-ischemic skin hyperemia improved with pGz therapy (p < .05). Four weeks after discontinuation of pGz, most therapeutic effects had vanished in both patient groups. Conclusions: In patients with severe heart failure and with leg claudication who remain symptomatic despite maximal medical therapy and who were not candidates for surgery, periodic acceleration applied over several weeks improved quality of life and exercise capacity. The clinical benefits appear to be mediated through improved endothelial function.

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