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SEVENTH FRAMEWORK PROGRAMME

The Project - WP 13 Cellular mechanisms and therapy

Objectives

To study novel therapeutic options on a cellular level.

WP13 plans to achieve the following objectives: 

  • to assess effects of the a) physical, b) chemical and c) biological factors on the bone marrow stem and progenitor cells with regards to their proliferation capacity and differentiative potential (Task 1); 
  • to study the "reversibility" of cellular models of heart failure, diabetes mellitus, and obesity (Task 2);
  • to create a system of criteria allowing the estimation of the regenerative potential of a given patient's own stem cells (Task 3); 
  • to create a preliminary design for future clinical trials aiming at the assessment of the established system of criteria (Task 4). Experience and data accumulated during tasks 1-3(together with data provided by other WPs, most importantly WP12 (Molecular pathways, cell culture) and WP14 (Vascular research, ex vivo) , will build the basis for task 4 studies that are, however, not primarily part of the SICA-HF protocol and will only be performed if time permits. The primary aim of WP 13 is to achieve a comprehensive characterization of the cell systems employed by advanced techniques of cellular physiology and biochemistry. The results of previous studies and data from pilot experiments will be utilized to attain a high standard of characterization in both qualitative and quantitative aspects of complex cell systems. Furthermore, technological and analytical expertise provided by (MC) would become an invaluable addition for making characterization more versatile and complete. Results achieved within WP13 will be cross-fed to all other WPs, primarily to WP12 (Molecular pathways, cell culture) and WP14 (Vascular research, ex vivo).

Workpackage Leader: St. Petersburg
Involved Partners: CharitÚ, Tomsk, Moscow CRC

Workpackage description

Regenerative and adaptive processes that take place in the myocardium and in myocardial blood vessel walls require active participation of the body's own stem and progenitor cells. These cells act as a substrate of tissue regeneration or rearrangement in a form of response to all physiological or pathological stimuli. In heart failure and diabetes mellitus with or without associated body weight changes, various factors influence the generation of bone marrow stem and progenitor cells. These factors include a) physical (variations in the oxygenation level), b) chemical (a dysbalance of nutrient levels) and c) biological factors (a shift in growth factor expression levels). These factors could alter the proliferative potential of the latter cells, as well as their potential to differentiate to functional (mature) cells. As a result, there is an inadequacy of bone marrow stem and progenitor cells' regenerative and adaptive potential that could contribute to the progress of heart failure in patients with metabolic alterations.

We hypothesize that metabolic alterations observed in heart failure with diabetes mellitus with or without associated body weight changes (e.g., variations in the oxygenation level, in blood glucose, nutrients deficiency, excess of lipids and triglycerides, protein catabolism) can alter the proliferative and differentiative potential of bone marrow stem and progenitor cells. Among the latter, haematopoietic and mesenchymal (stromal) stem cells (HSCs & MSCs, respectively) and endothelial precursor cells (EPCs) are most appealing. The hypothesis outlined above will be specifically addressed using cellular models (in vitro models) of metabolic alterations. Numerous factors (physical and biological) will be applied into the modes in a reversible manner. Importantly, SCs and PCs will be evaluated in both healthy (control group) and affected subjects. Adult patients with diastolic heart failure, with or without diabetes mellitus and associated body weight changes  (obesity)  will be included in the study. The results of our study will allow establishing criteria for the estimation of the regenerative potential a patient's own stem cells. Such criteria are meant to serve as a means to predict the effectiveness of cell therapy in any given patients. Further, these criteria may serve in the selection of the right therapeutic avenue (prognostics, therapeutic options) in the respective patient. Although data are lacking for patients with heart failure in general, it appears to be particularly important to study patients with the disease and co-morbidities such as type 2 diabetes, obesity or cachexia. That would be essential to understand basic mechanisms underlying cell factor contribution to the pathogenesis of the disease and to develop a practical cell therapy-based therapeutic approach targeting these groups of patients in the future.

Task 1 (Months 13-24).

Over this part of the WP13 studies, we aim to assess effects of the a) physical, b) chemical and c) biological factors on the bone marrow stem and progenitor cells with regards to their proliferation capacity (by rate of expansion analysis) and differentiative potential (ability to differentiate into a) osteogenic, b) adipogenic, c) neural and d) endothelial progeny). Trophic/support (microvironmental) function of MSCs will be specifically evaluated in co-culture studies (AC). We will first study patient-derived bone marrow stem cells and progenitor cells cultured in vitro (AC, collected from +100 adult men & women including +75 patients with HF, diabetes mellitus & metabolic syndrome, and +25 healthy controls). In addition, we will use "cellular models" of 1) heart failure (reduced oxygen tension, reduced nutrient levels in a culture media), 2) type 2 diabetes mellitus (altered glucose and insulin levels), 3) obesity (excessive levels of lipids and triglycerides) and 4) cachexia (nutrient deficiency). In this case, bone marrow stem and progenitor cells (including endothelial precursor cells) will be cultured in vitro in these pre-specified culture conditions. An assay of modern immunocytochemistry, genetics and proteomics-based technologies (by CD141, CD144, FGFR1, vWF, CFSE, BrDU incorporation, etc.) will be employed to assess an impact of physical, chemical and biological factors on proliferation capacity and differentiative potential of the cells. Our models represent both actual clinical cases and "cellular models" of heart failure, type 2 diabetes mellitus and associated body weight changes. In particular, bone- and adipose-tissue related growth factors affecting  MSCs and EPCs will be studied (AC). To supplement in vitro data, cell properties of MSCs derived from fat tissue of various localization (CRC, collected from adult men & women including patients with HF, diabetes mellitus & metabolic syndrome, and healthy controls) and of actual myocardium (derived from myocardial biopsies executed for clinical purposes; CT, collected from adult men & women) will be studied using an assay of the modern physiology and immunobiology-related techniques (with CRC partner acquiring a leading role in this particular part of the study). Autophagy of myocardial and hematopoietic cells (as a marker of disturbed protein metabolism) will be evaluated. Interactions of EPCs and MSCs  will be studied for the evaluation of mechanisms of myocardial fibrosis (AC, CRC). Bone and adipose tissue-derived growth factors (most importantly, BMP family factors) will be assessed as key players in this mechanism. Both WP13 partners (AC and MC) will interact closely in the work for this task, with available technical platforms and personnel expertise utilized to achieve rapid progress of the study. Additionally, data generated by the following key participants will contribute to the studies performed at this stage: WP05, WP07, WP08, WP09 and WP10 (all by providing essential data on the physiological parameters characteristic to particular clinical states), WP12 and WP14 (by providing essential data on the physiological parameters characteristic to the cellular systems studied within their own research objectives).

Task 2 (Months 18-36).

Studies of the "reversibility" of cellular models of heart failure with type 2 diabetes mellitus, obesity and/or cachexia will be performed at this stage of WP13 (AC). We will assess the ability of cultured bone marrow stem and progenitor cells to recover their properties following the extinction of disturbing metabolic factors (again, as applied to cellular/in vitro models). Recovery of such cells will be assessed particularly with regards to the proliferative potential and functional properties (including differentiation abilities and angiogenesis) of progenitor cells under in vitro conditions. Based on the results achieved at this stage of WP13, transplantation of allogenic MSCs will be considered as one of the treatment options applied on the consecutive stages of the project. Again, both WP13 partners (AC and MC) will interact closely with other SICA-HF participants (namely, MC (WP12) and CT (WP14)) in the work for this task. This includes an exchange of data generated over the course of the individual WPs that is useful for the progress of the partner.

Task 3 (Months 31-36).

The aforementioned tasks will enable us at this stage of the work package to implement a system of criteria that allows estimating the regenerative potential of a given patient's own stem cells. The establishment of such a system of criteria would be most important with regards to predict the effectiveness of cell therapy for patients with heart failure in a particular clinical situation (i.e., with or without diabetes mellitus and body mass changes). In the particular clinical cases, utilization of such a system would allow the definition of an appropriate approach to cell therapy (for example, autological or allogenic cell material transplantation-based, application of growth factors). Access to the clinical information available for both WP13 partners (AC and MC) will be invaluable at this stage of WP13. The following key participants will contribute to the studies performed on this stage: WP03, WP05 and WP10 (all by all by providing essential data on the clinical features (measurable by instrumental means) characteristic to the particular clinical states). Additionally, AC (WP15) will potentially contribute data to be utilized to complement available lists of genetic diagnostic/prognostic markers.

Task 4 (Months 37-54).

An effectiveness of the established system of criteria could be assessed in clinical trials. Over the course of the trials of such a scale, randomized groups of patients with heart failure and/or diabetes mellitus could be transplanted with autological or allogenic cell material (bone marrow stem cells or individual fractions of the latter). In the group of participants with heart failure, an effect of growth factor administration-based therapy could also be assessed. Non-interventional and interventional means of control (including myocardial biopsy) could then be routinely utilized to evaluate the results of transplantation-based cell therapy. Task 4 aims at utilizing results achieved to make a preliminary design for such a trial, to be executed some time in the future (once essential safety and ethical issues are fully resolved). WP13 partners (AC and MC) will most closely interact in working over this task. Furthermore, data generated by other project participants over the course of the overall project will be analyzed critically in the clinical trial design step. To ensure effective coordination and interaction of individual participants (most importantly, WP03, WP04 and WP10), a role of MR/GABO (WP11) will be indispensable.

WP 13 Cellular mechanisms and therapy