• células-tronco mesenquimais
• medicina regenerativa
• isquemia miocárdica
• terapia baseada em transplante de células e tecidos

• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Myocardial Ischemia/therapy
• Adipose Tissue/cytology
• Treatment Outcome
• Mesenchymal Stem Cells/cytology

• Cell survival
• Cell therapy
• Pre-treatment
• Preconditioning
• Stem cells
• Super stem cells

• Injections
• Stem cells
• Stress tolerance
• Tardigrade
• Transgenic

• Animals
• Humans
• Cell Survival/drug effects
• Stem Cells/metabolism
• Stem Cells/cytology
• Cell Differentiation
• Tardigrada/metabolism
• Adipose Tissue/cytology
• Adipose Tissue/metabolism
• Mitochondrial Proteins/metabolism
• Mitochondrial Proteins/genetics
• Mitochondria/metabolism
• Adipogenesis
• Cells, Cultured
• Stress, Physiological

• EDUC4-12752 California Institute for Regenerative Medicine
• GRFP1000307418 Directorate for Engineering
• 19IPLOI34760636 American Heart Association
• California Space Grant Consortium

• adipose tissue-derived mscs
• angiogenesis
• cardiac repair
• cardiac stem cells
• challenges
• induced pluripotent stem cells
• ischemic heart disease
• mesenchymal stem cells
• stem cells
• umbilical cord-derived mscs

• adipose
• atherosclerosis
• heart disease
• inflammation
• oxidative stress
• stem cells

• Humans
• MicroRNAs/metabolism
• Cardiovascular Diseases/therapy
• Cardiovascular Diseases/metabolism
• Metabolic Reprogramming
• Diabetes Mellitus, Type 2/metabolism
• Mesenchymal Stem Cells/metabolism
• Aging
• Stem Cells/metabolism
• Inflammation/pathology

• Cardiac tissue engineering
• Encapsulation
• Exosomes
• Hydrogels
• Infarction
• Regeneration

• IR.NIMAD.REC.1400.151 National Institute for Medical Research Development
• IR.TBZMED.REC.1399.125 Tabriz University of Medical Sciences

• ADSCs
• adipose tissue
• immunomodulatory cytokines
• lipoaspirates
• mechanical dissociation
• mesenchymal stem/stromal cells
• regenerative medicine

• Adipose tissue derived mesenchymal stromal cells
• Allogeneic cell therapy
• Heart failure
• Ischaemic heart disease
• Randomized clinical trial
• Stem cell

• stem-cell research
• mesenchymal stem cells

• Adipose Tissue
• Cell Differentiation/genetics
• Humans
• Mesenchymal Stem Cells
• Regenerative Medicine
• Umbilical Cord

• Vingroup Scientific Research and Clinical Application Fund (Grant number: PRO.19.47)

Adipose tissue-derived stromal cells (ASCs) are of interest in tissue engineering and regenerative medicine (TERM) due to their easy acquisition, multipotency, and secretion of a host of factors that promote regeneration. Retention of ASCs in or around lesions is poor following direct administration. Therefore, for TERM applications, ASCs can be ‘immobilized’ via their incorporation into hydrogels such as gelatine methacryloyl (GelMA). Tweaking GelMA concentration is a common approach to approximate the mechanical properties found in organs or tissues that need repair. Distinct hydrogel mechanics influence the ability of a cell to spread, migrate, proliferate, and secrete trophic factors. Mesenchymal cells such as ASCs are potent remodellers of the extracellular matrix (ECM). Not only do ASCs deposit components, they also secrete matrix metalloproteases (MMPs) which degrade ECM. In this work, we investigated if GelMA polymer concentration influenced the expression of active MMPs by ASCs. In addition, MMPs’ presence was interrogated with regard to ASCs morphology and changes in hydrogel ultrastructure. For this, immortalised ASCs were embedded in 5%, 10%, and 15% (w/v) GelMA hydrogels, photopolymerised and cultured for 14 d. Zymography in situ indicated that MMPs had a variable, hydrogel concentration-dependent influence on ASCs-secreted MMPs. In 5% GelMA, ASCs showed a high and sustained expression of MMPs, while, in 10% and 15% GelMA, such expression was almost null. ASCs morphology based on F-actin staining showed that increasing GelMA concentrations inhibit their spreading. Scanning electron microscopy (SEM) showed that hydrogel ultrastructure in terms of pore density, pore size, and percentage porosity were not consistently influenced by cells. Interestingly, changes in ultrastructural parameters were detected also in cell-free materials, albeit without a clear trend. We conclude that hydrogel concentration and its underlying mechanics influenced MMP expression by ASCs. The exact MMPs that respond to these mechanical cues should be defined in follow-up experiments.

• GelMA
• adipose tissue-derived stromal cells
• hydrogels
• matrix metalloproteases
• stiffness
• stress relaxation

The emerging field of advanced therapy medicinal products (ATMP) holds promise of treating a variety of diseases. Adipose-derived stromal cells (ASCs) are currently being marketed or tested as cell-based therapies in numerous clinical trials. To ensure safety and efficacy of treatments, high-quality products must be manufactured. A good manufacturing practice (GMP) compliant and consistent manufacturing process including validated quality control methods is critical. Product design and formulation are equally important to ensure clinical feasibility. Here, we present a GMP-compliant, xeno-free, and semiautomated manufacturing process and quality controls, used for large-scale production of a cryopreserved off-the-shelf ASC product and tested in several phase I and II allogeneic clinical applications.

• fibroblast
• integration analysis
• mesenchymal stromal cells
• pericytes
• single-cell transcriptome sequencing

• the National Natural Science Foundation of China
• Shenzhen Key Projects of Basic Research
• National Science and Technology Major Project
• Science and Technology Projects of Guangdong Province
• Shenzhen Industry and Information Committee “Innovation Chain and Industry Chain” integration special support plan project
• the Sanming Project of Medicine in Shenzhen

Mesenchymal stem/stromal cells (MSCs) are widely described in the context of their regenerative and immunomodulatory activity. MSCs are isolated from various tissues and organs. The most frequently described sources are bone marrow and adipose tissue. As stem cells, MSCs are able to differentiate into other cell lineages, but they are usually reported with respect to their paracrine potential. In this review, we focus on MSCs derived from adipose tissue (AT-MSCs) and their secretome in regeneration processes. Special attention is given to the contribution of AT-MSCs and their derivatives to angiogenic processes described mainly in the context of angiogenic dysfunction. Finally, we present clinical trials registered to date that concern the application of AT-MSCs and their secretome in various medical conditions.

• MSCs secretome
• angiogenesis
• mesenchymal stem cells
• tissue regeneration

• Cell Differentiation
• Clinical Trials as Topic
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Neovascularization, Physiologic
• Regeneration
• Secretome/metabolism

• FDA regulations
• bone marrow aspirate concentrate (BMAC)
• cancer
• cell therapy
• immune diseases
• mesenchymal stem cells
• multicellular therapies
• regenerative medicine

• Autologous stem cells
• Cell therapy
• Diabetes
• Ischemic heart disease
• Microvessicles
• Regenerative potential

While existing remedies failed to fully address the consequences of heart failure, stem cell therapy has been introduced as a promising approach. The present review is a comprehensive appraisal of the impacts of using mesenchymal stem cells (MSCs) in clinical trials mainly conducted on ischemic cardiomyopathy. The benefits of MSC therapy for dysfunctional myocardium are likely attributed to numerous secreted paracrine factors and immunomodulatory effects. The positive outcomes associated with MSC therapy are scar size reduction, reverse remodeling, and angiogenesis. Also, a decreasing in the level of chronic inflammatory markers of heart failure progression like TNF-α is observed. The intense inflammatory reaction in the injured myocardial micro-environment predicts a poor response of scar tissue to MSC therapy. Subsequently, the interval delay between myocardial injury and MSC therapy is not yet determined. The optimal requested dose of cells ranges between 100 to 150 million cells. Allogenic MSCs have different advantages compared to autogenic cells and intra-myocardial injection is the preferred delivery route. The safety and efficacy of MSCs-based therapy have been confirmed in numerous studies, however several undefined parameters like route of administration, optimal timing, source of stem cells, and necessary dose are limiting the routine use of MSCs therapeutic approach in clinical practice. Lastly, pre-conditioning of MSCs and using of exosomes mediated MSCs or genetically modified MSCs may improve the overall therapeutic effect. Future prospective studies establishing a constant procedure for MSCs transplantation are required in order to apply MSC therapy in our daily clinical practice and subsequently improving the overall prognosis of ischemic heart failure patients.

• Clinical trials
• Ischemic cardiomyopathy
• Mesenchymal stem cells

• angiogenic exosomes
• cardiac regeneration
• cell therapy
• myocardial infarction
• stem cell

• Angiogenesis Inducing Agents/therapeutic use
• Animals
• Disease Models, Animal
• Exosomes/metabolism
• Heart Diseases/metabolism
• Heart Diseases/therapy
• Rats
• Stem Cell Transplantation/methods
• Zebrafish

• Autocrine
• Endocrine
• Mesenchymal stem cells
• Paracrine
• Remote delivery

• Adipose-derived stem cells
• Ex vivo culture-expanded stem cells
• Mesenchymal stem cells
• Regenerative therapies
• Scaffold free-cellsheet technology
• Scaffold-based cellsheet technology
• Tissue derived stem cells
• Tissue engineering

• adipose
• angiogenesis
• differentiation
• stem
• vascularization

• Adipose Tissue/cytology
• Animals
• Cell Differentiation
• Cell Proliferation
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/physiology
• Neovascularization, Physiologic

• Large animal
• Mesenchymal stem cell
• Myocardial infarction
• Osteoarthritis

• Animals
• Animals, Laboratory
• Cell- and Tissue-Based Therapy
• Disease Models, Animal
• Humans
• Laboratories
• Mesenchymal Stem Cells/cytology

• Horizon 2020

• Heart failure
• Ischaemic heart disease
• Mesenchymal stromal cell
• Randomized clinical trial
• Stem cell

• Anti-fibrotic mechanisms of action
• Clinical trials
• Fibrosis
• Heterogeneity
• Mesenchymal stromal cells
• Pre-clinical animal models

Stem cell therapy is investigated as a treatment option for patients with ischemic heart disease. In this study, long-term safety and efficacy of autologous intra-myocardial injections of adipose-derived stromal cells (ASCs) was studied in patients with refractory angina.

Sixty patients with coronary artery stenosis and preserved left ventricular ejection fraction were 2:1 randomised to intramyocardial injections of ASCs or saline and followed for 3 years.

For patients in the ASC group, the bicycle exercise time and the exercise performance in watt were un-changed (383 ± 30 s to 370 ± 44 s, P = 0.052 and 81 ± 6 to 78 ± 10, P = 0.123, respectively), but the performance in METs was reduced significantly (4.2 ± 0.3 to 4.0 ± 0.4, P = 0.027) during the follow-up period. However, in the same period, there was in the placebo group a significant decline in bicycle exercise time (437 ± 53 s to 383 ± 58 s, P = 0.001), the exercise performance measured in watt (87 ± 12 W to 80 ± 12 W, P = 0.019) and in METs (4.5 ± 0.4 to 4.1 ± 0.4, P = 0.002). Moreover, angina measured as CCS class was significantly reduced in the ASC group but not in the placebo group (2.5 ± 0.9 to 1.8 ± 1.2, P = 0.002 and 2.5 ± 0.8 to 2.1 ± 1.3, P = 0.186, respectively). However, no significant change was observed between the two groups.

Patients receiving ASCs had improved cardiac symptoms and unchanged exercise capacity, in opposition to deterioration in the placebo group.

Trial registration ClinicalTrials.gov Identifier: NCT01449032. Registered 7 October 2011—Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT01449032?term=jens+kastrup&rank=7

• Adipose derived stromal cells
• Chronic ischemic heart disease
• Refractory angina
• Regeneration
• Stem cell therapy

Adipose-derived stromal cell (ASC) therapy is currently investigated as a new treatment option for patients with ischemic heart disease (IHD). The aim of this study was to evaluate the effect of ASC therapy in patients with chronic IHD measuring myocardial perfusion and cardiac function using cardiac magnetic resonance imaging (CMRI). Patients were included in MyStromalCell trial, a phase II, randomized, double-blinded, placebo-controlled study investigated the effect of ASCs in patients with chronic IHD with preserved left ventricular ejection fraction (LVEF). In total, 41 of 60 patients underwent cine, late enhancement, rest and stress imaging with CMRI. There was a non-significant difference between stress and rest values in maximal signal intensity, a measure of myocardial perfusion, from baseline to follow-up comparing placebo with ASC group (–52.52 ± 88.61 and 3.05 ± 63.17, p = 0.061, respectively). LVEF, myocardial mass, stroke volume, left ventricle end-diastolic volume and end-systolic volume changed non-significantly (–0.5 ± 4.7%, –3.5 ± 13.1 g, –0.7 ± 8.6 mL, 1.9 ± 25.1 mL and 2.6 ± 16.5 mL, respectively) in the placebo group and in the ASC group (0.7 ± 8.6%, 0.9 ± 10.8 g, –0.3 ± 26.1 mL, –3.0 ± 31.5 mL and –2.7 ± 20.4 mL, respectively) from baseline to 6 months follow-up. The amount of scar tissue was unchanged in the placebo group by 0.0 ± 1.6 g, p = 1.0 and in the ASC group with –0.3 ± 2.3 g, p = 0.540. There was no difference between the groups. There was a non-significant trend toward increased myocardial perfusion but no significant changes in functional parameters or amount of scar tissue in patients treated with ASCs compared with patients allocated into the placebo group.

• adipose-derived stromal cell
• cardiac magnetic resonance imaging
• coronary artery disease
• mesenchymal
• randomized clinical trial
• stem cell therapy

• Extracellular matrix (ECM)
• adipose tissue
• adipose tissue-derived stromal cells (ASC)
• hydrogel

Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage.

• Adipose-derived stem cells
• Ischemic heart diseases
• Myocardial repair
• Paracrine effects
• Secretome
• Strategies

• adipose tissue stem cells
• clinical application
• culture
• isolation
• stem cell therapy
• storage

• cell therapy
• stroke
• stromal vascular fraction

• Adipose-derived stromal cells
• Allogeneic therapy
• Clinical trial
• Heart failure
• Ischaemic cardiomyopathy
• Stem cells

• Analgesics
• Elderly population
• Frailty
• Osteoarthritis
• Pain
• Stromal vascular fraction

Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach.

• cardiac clinical trials
• cardiac regeneration
• cell therapy
• heart dysfunction
• heart failure
• stem cells
• translational medicine

Ischemic heart disease is a major cause of death and disabilities worldwide. Unfortunately, not all patients are suitable for direct revascularization. Cell-based therapies may be alternative options because of their potential to promote neovascularisation and endothelial repair, improving myocardial perfusion. The success of cell-based therapies depends on the type of implanted stem cells, delivery method and underlying disease. Several different cell populations including bone marrow-derived mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), CD34+, CD133+, endothelial progenitor cells, adipose-derived mesenchymal stromal cells (ASCs) and stem cells from placenta and umbilical cord have been investigated. Presently, no consensus exists about the best cell type for clinical regenerative therapy. Because the system of coronary arteries in the ischemic area is poor and most of the coronary artery is significantly narrowed or closed, direct implantation of stem cells in the ischemic area of the heart muscle appears an attractive method.

• ischemic heart disease
• regenerative medicine
• stem cells

• cardiovascular disease
• mesenchymal stem cell
• regenerative medicine