Advanced Regenerative Medicine

Cardiovascular Disease

Myocardial infarction (MI) causes the loss of cardiac tissue and scar formation, which ultimately lead to heart failure.

Cardiology

Myocardial infarction (MI) causes the loss of cardiac tissue and scar formation, which ultimately lead to heart failure. According to the World Health Organization, heart failure initiated by MI and coronary artery disease accounts for 29% of deaths worldwide. However, human heart tissue does not regenerate spontaneously, thus “regenerative medicine” represents a promising alternative treatment for MI. Cardiac tissue regenerative medicine involves cardiomyocyte regeneration, neovascularization, and paracrine cytokines, which have anti-inflammatory, anti-apoptotic, and anti-remodelling effects. During the last decade, stem cells have become promising candidates for regenerative medicine not only because of their capacity of differentiation toward cardiomyocyte and vascular cell lineages but also their capacity for releasing such paracrine factors and their anti-arrhythmic effects. Paracrine cytokines and chemokines play pivotal roles in stem cell related cardiac repair mechanisms.

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) have been proposed as an optimal regenerative cellular therapeutic for degenerative musculoskeletal conditions like OA. These cells are found in a variety of tissues and have the ability to rapidly proliferate and differentiate to musculoskeletal lineages including bone and cartilage. A significant body of research has also demonstrated that these cells orchestrate important immunologic functions through modulation of the local inflammatory response. Taken together, these factors support the theoretical ability of MSCs to deter degenerative joint disease.

Safety

Adipose tissue-derived mesenchymal stem cells (Ad MScs) represent an attractive and ethical cell source for stem cell therapy. With the recent demonstration of MSC homing properties, intravenous applications of MSCs to cell-damaged diseases have increased. The toxicity and tumourigenicity of human Ad MScs were investigated for clinical application. Culture-expanded hAdMSCs showed the typical appearance, immunophenotype, and differentiation capacity of MSCs, and were genetically stable at least 12 passages in culture. Cells suspended in physiological saline maintained their MSC properties in a cold storage condition for at least 3 days. To test the toxicity of hAdMSCs, different doses of hAdMSCs were injected intravenously into immunodeficient mice, and the mice were observed for 13 weeks. Even at the highest cell dose (2.5×10(8) cells/kg body weight), the SCID mice were viable and had no side effects. A tumourigenicity test was performed in Balb/c-nu nude mice for 26 weeks. Even at the highest cell dose (2×10(8) MSCs/kg), no evidence of tumour development was found. In a human clinical trial, 8 male patients who had suffered a spinal cord injury >12 months previous were intravenously administered autologous hAdMSCs (4×10(8) cells) one time. None of the patients developed any serious adverse events related to hAdMSC transplantation during the 3-month follow-up. In conclusion, the systemic transplantation of hAdMSCs appears to be safe and does not induce tumour development.

Secretome

The use of MSCs for tissue repair was initially based on the hypothesis that these cells home to and differentiate within the injured tissue into specialized cells. However, it now appears that only a small proportion of transplanted MSCs actually integrate and survive in host tissues. Thus, the predominant mechanism by which MSCs participate in tissue repair seems to be related to their paracrine activity. Indeed, MSCs provide the microenvironment with a multitude of trophic and survival signals including growth factors and cytokines. Recent discoveries suggest that lipid microvesicles released by MSCs may also be important in the physiological function of these cells. Over the past few years the biological relevance of micro- and nano-vesicles released by cells in intercellular communication has been established. Alongside the conventional mediators of cell secretome, these sophisticated nanovesicles transfer proteins, lipids and, most importantly, various forms of RNAs to neighbouring cells, thereby mediating a variety of biological responses.

Patented Production Method

Previous studies suggest that a hypoxic condition promotes self-renewal of undifferentiated mesenchymal stem cells and enhances their therapeutic potential. Our ExoRAP and ExoPAN technology uses a protocol of pre-treatment of the cultured MSC in special media and various anoxia conditions instead of hypoxia. With this protocol a 30 fold increase in RNA content per cell can be achieved. The technology is successfully being used in regenerative treatments in human ExoRAP and ExoPAN technology and animal patients.

Preclinical studies regarding Heart Disease

The human heart has limited regenerative capacity, which makes the reparative response after the cardiac infarction quite challenging. During the last decade, stem cells have become promising candidates for heart repair, owing to their potent differentiation capacity and paracrine cytokine secretion. Among the different types of stem cells, mesenchymal stem cells have high proliferative potential and secrete numerous cytokines, growth factors, and microRNAs. The paracrine cytokines play important roles in cardiac regeneration, neovascularization, anti-apoptosis, and anti-remodeling mechanisms, among others. Preclincal studies showed that adipose derived mesenchymal stem cells were effective in mitigating DOX-induced cardiac damage by promoting angiogenesis, decreasing the infiltration of immune cells and collagen deposition. Moreover, cell free secretome containing exosomes stimulates neovascularization and restrains the inflammation response, thus improving heart function after ischemic injury.

Our own preclinical studies on cardiomyocytes

Preclinical In vitro investigation of the influence of the ad-MSC secretome on the apoptosis of isolated cardiomyocytes after Glucose and Oxygen Deprivation:
Several studies have reported that micro RNA is involved in the pathogenesis and progression of ischaemic diseases and that miR-22 may inhibit the inflammatory response and cell apoptosis. In our model, we are using primary cardiomyocytes which will be subjected to glucose and oxygen deprivation with or without the addition of the ad-MSC secretome containing mRNA, miRNA and cytokines.
The effect will be measured by the Lonza Toxilight test and the apoptosis , necrosis and healthy cell detection kit by Promokine, and ELISA assays on TNF-alpha, Caspase 9, Blc-2 and NF-KappaB p65. Additionally, ELISA assays on cardiac troponin I, C-reactive protein, myoglobin and proBNP will be performed.

Clinical studies on Heart Disease

Recent studies suggest that the intracoronary administration of bone marrow (BM)-derived mesenchymal stem cells (MSCs) may improve left ventricular function in patients with acute myocardial infarction (AMI). However, there is still argumentative for the safety and efficacy of MSCs in the AMI setting. Transplantation of selected MSCs for patients with AMI was shown to be safe and induces an increase in LVEF with a limited impact on left ventricular remodeling. Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. The main difficulty in assessing these clinical trials are the absence of a defined secretome and the great variation in performance of MSCs. Trails with our own secretome, where compete miRNA expression profile and cytokine analysis is available will without doubt show differences in the efficacy within different production methods.

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