Cardio-Thoracic Translational Medicine (CTTM) Laboratory
Main areas of research:
Extracellular matrix landscape of the heart in health and pathology
Extracellular matrix (ECM) is a secreted product that provides the cells with not only simple anchoring points, but also affects their survival, function and expression of proteins. Thus, ECM is a relatively fixed in space entity that is in a constant crosstalk with the local cellular milieu and, similar to fossils, may store molecular traces of the local pathophysiological processes.
To elucidate this hypothesis, we use several approaches. We have initiated an observational experimental clinical study on patients undergoing aortic valve replacement for isolated valve degeneration to analyze ECM from the valves and biomarkers in the blood (the BAV/TAV study). The study includes both patients with degeneration of normal tricuspid aortic valve (TAV) and abnormal valves such as bicuspid (BAV) and monocuspid aortic valve. We isolate the ECM fractions from the aortic valves collected during the operations and analyze them using several proteomic approaches such as mass spectrometry, Western blotting and immunostaining. Our goal is to include 200 patients and generate a unique collection of biological material from the aortic valve. Results of the analysis will be used to design novel treatments of aortic valve degeneration prompting interventional clinical trials at the Akademiska Hospital.
Another approach is to analyse ECM from the heart and large vessels in healthy animals and animal models of various cardiovascular diseases. Our lab has a unique experience in modelling of myocardial infarction (MI) and the reperfusion injury after MI. We use the models to compare the ECM from normal and the diseased animals.
Prevention of long-term complications of aortic stenosis and regurgitation
Our team also investigates on the long-term consequences of aortic stenosis and regurgitation on the heart function. We hypothesize that the BAV patients, although younger at the time of surgery, have more prevalent and more severe myocardial dysfunction which is partly irreversible. The main reason is that BAV patients are usually operated too late. Therefore, it is important to find BAV patients before presentation of the symptoms and define parameters for operation of the patients in time. In order to address this hypothesis, we evaluate the patients from the BAV/TAV study by directed transthoracic echocardiography before and one year after surgery. To assess the heart function, we evaluate a wide range of parameters reflecting systolic and diastolic dysfunction in combination with lab analyses of the biopsies. The findings are compared and validated to retrospective data of already operated patients using registry cohorts such as the SWEDEHEART registry.
Treatment of acute respiratory distress syndrome with mesenchymal stromal cells (MSCs)
Viral pandemics such as SARS, MERS, H1N1 and SARS-CoV-2 have detrimental medical and economical effects on society. The main causes of death are pneumonia or Acute Respiratory Distress Syndrome (ARDS) that is a life-threatening condition characterized by uncontrolled bilateral inflammatory response with infiltrations in the lungs followed by non-cardiac hypoxemic respiratory failure. The syndrome accounts for more than 10% of intensive care unit admissions worldwide, has a mortality exceeding 40% in the most severe cases and does not have a treatment. The extremely hypoxemic patients are stabilised with extracorporeal membrane oxygenation (ECMO), but it does not decrease their 60-day mortality. Another growing need is to prevent the long-term neuromuscular, mental and respiratory complications that are common among the ARDS survivors.
In 2015, we reported the successful use of systemic administration of a single dose of minimally expanded allogeneic bone marrow derived MSCs from one donor on two patients with severe ARDS on ECMO support1. In a follow-up study, we demonstrated that, five years after the treatment, both patients have fully recovered their physical and mental capacities, with normalization of their lung functions2. This is unusual for ARDS survivors and suggests that infusion of MSCs may not only reduce mortality, but also protect from long-term adverse effect of the disease.
To test the hypothesis, we have initiated a clinical study of bone marrow derived MSC therapy for the treatment of acute respiratory distress syndrome induced by SARS-CoV-2. After informed consent, the patients that develop moderate-to-severe ARDS and receive invasive mechanical ventilation are treated with MSCs. Both results of medical tests and biological samples will be analysed to determine safety and efficacy of the treatment.
Long-term culturing of biologically active MSCs
Another major hurdle for therapies involving MSCs is limited supply of the cells. Standard methods of in vitro culturing lead to a sharp decline in the ability of MSCs to orchestrate the immune system and provide enough cells for treatment of only a few patients per one donor of the cells. Donor-to-donor variability does not allow to produce large amounts of MSCs for treatment of significant cohorts of patients that complicates both scientific research and regulatory workflow for approval of the clinical trials.
To address the problem, we use recombinant proteins from the perivascular niche for in vitro culturing of MSCs. This approach enables long-term cultures of MSCs providing hundreds of thousands of therapeutic doses of the immunomodulating cells from cell material taken from only one donor.
Members of the research group 2021
Prof Elisabeth Ståhle, MD, PhD
Prof Karl-Henrik Grinnemo, MD, PhD
A/Prof Sergey Rodin, PhD - group leader
Oscar Simonson, MD
Ulrika Felldin, MSc
Sandeep Kadekar, PhD
Johan Wedin, MD, PhD student
- Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalén M, et al. In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome. Stem Cells Transl Med 2015;4:1199–1213. doi:10.5966/sctm.2015-0021.
- Simonson OE, Ståhle E, Hansen T, Wedin JO, Larsson A, Mattsson M, et al. Five-year follow-up after mesenchymal stromal cell-based treatment of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2020;202:1051–1055. doi:10.1164/rccm.202003-0544LE.