Cardiometabolic diseases, such as cardiovascular disease, type 2 diabetes and hypertension, are the number one cause of death in the western world, thus posing a need for novel therapies. Despite recent progress in treatment options for cardiometabolic diseases, the clinical prognosis of e.g. heart failure is currently worse than that of most cancers. Blood vessels are essential in all tissues for the delivery of oxygen and nutrients. Recent studies have demonstrated that blood vessels are much more than an inert conduit for blood flow. Instead, endothelial cells lining the vessels are active regulators of tissue growth, metabolism and regeneration.
We want to understand how the interaction between endothelial cells and other cell types is regulated in the healthy heart and skeletal muscle, and how their relationship is disturbed in cardiovascular and metabolic diseases. We use induced pluripotent stem cells from human patients to model these interactions in cell cultures, and to study the effects of genetic mutations that cause heart disease. The goal of our studies is to deepen our understanding on vascular biology, and to identify novel therapeutic targets in endothelial cells in cardiometabolic diseases.
We are also interested in skeletal muscle stem cell differentiation and skeletal muscle physiology and pathology, with a special focus on the role of the Prox1 transcription factor. Our aim is to understand the role and function of Prox1 in skeletal muscle physiology and in rhabdomyosarcoma, which is a highly malignant pediatric cancer.
Vascular and muscle biology in cardiometabolic diseases
Endothelial cells in different organs express a unique combination of transcription factors, angiogenic growth factors, adhesion molecules and chemokines. The organotypic vasculature reflects the varying needs of different organs, for example, oxygen and nutrient supply. In response to various stimuli, endothelial cells secrete a set of proteins, which can act on the neighboring cell types. Humans have approximately 100 000 km of blood vessels, which likely makes the vasculature the largest “endocrine organ” in the body.
Our group has a specific interest in the crosstalk between endothelial cells and cardiomyocytes as well as skeletal muscle fibers. We want to know: 1) how this interaction is regulated in healthy tissues and during physiological growth, 2) how it is affected by aging, obesity, heart failure and exercise, and 3) how impairment in this crosstalk contributes to the development of cardiometabolic diseases and 4) how it could be targeted with therapeutics.
Modeling cardiovascular physiology and pathology using human induced pluripotent stem cells
Recapitulating the tissue microenvironment is a central challenge in the development of experimental disease models. To provide reliable tools for mechanistic studies, for drug development and for personalized treatments, it is critical to create an environment that consists of several cell types to model the tissue microenvironment in vivo.
Using patient-derived induced pluripotent stem cells (iPSC), we construct microtissues, where iPSC-derived endothelial cells are cultured together with iPSC-derived cardiomyocytes in 2D and 3D models. Furthermore, we expose the endothelial cells to flow-induced shear stress, mimicking in vivo conditions. We also examine genetic determinants of congenital heart disease in the Finnish patient population using next generation sequencing, CRISPR/Cas9 gene editing technology, and patient-derived iPSCs.
Regulation of skeletal muscle physiology and pathology by the Prox1 transcription factor
After damage, skeletal muscles have a remarkable capacity for regeneration. We have shown that the Prox1 transcription factor, which regulates stem cell behavior in various healthy and malignant tissues, is essential for slow muscle fiber type and satellite cell differentiation in skeletal muscle. Interestingly, several genome-wide association studies have also identified Prox1 as a candidate gene for type 2 diabetes in various populations.
We explore the mechanisms and relationships between Prox1 and muscle metabolism. Our studies on Prox1 mediated regulation of muscle stem cell differentiation should enhance the current understanding of muscle regeneration and satellite cell function, as well as the role of Prox1 in rhabdomyosarcoma.
Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells. Hemanthakumar KA, Fang S, Anisimov A, Mäyränpää MI, Mervaala E, Kivelä R.2021, Elife 10:e62678.
VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration. Räsänen M, Sultan I, Paech J, Hemanthakumar KA, Yu W, He L, Tang J, Sun Y, Hlushchuk R, HuanX, Armstrong E, Khoma OZ, Mervaala E, Djonov V, Betsholtz C, Zhou B, Kivelä R, Alitalo K. 2021, Circulation, 143: 65-77.
Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells. Helle E*, Ampuja M*, Antola L, Kivelä R. 2020, Front Physiol, 11:591450.
Angiogenesis and angiocrines regulating heart growth. Hemanthakumar KA, Kivelä R. 2020, Vasc Biol. 2(1): R93-R104.
Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2 -Mediated Paracrine Signaling. Kivelä R*, Hemanthakumar KA, Vaparanta K, Robciuc M, Izumiya Y, Kidoya H, Takakura N, Peng X, Sawyer DB, Elenius K, Walsh K, Alitalo K*. 2019, Circulation, 139:2570-2584.
Cardiomyocyte—Endothelial Cell Interactions in Cardiac Remodeling and Regeneration. Talman V, Kivelä R. 2018, Front Cardiovasc Med, 5:101.
Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. Hulmi JJ, Nissinen TA, Räsänen M, Degerman J, Lautaoja JH, Hemanthakumar KA, Backman JT, Ritvos O, Silvennoinen M, Kivelä R. 2018, J Cachexia, Sarcopenia, Muscle, 9:417-432.
The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre type regulation. Kivelä R, Salmela I, Nguyen YH, Petrova TV, Koistinen HA, Wiener Z, Alitalo K. 2016, Nat Commun, 7: 13124.
VEGF-B/VEGFR-1 induced expansion of adipose microvasculature counteracts obesity and related metabolic complications. Robciuc M, Kivelä R, Williams IM, de Boer JF, van Dijk TH, Elamaa H, Tigistu-Sahle F, Molotkov D, Käkelä R, Eklund L, Wasserman DH, Groen AK, Alitalo K. 2016, Cell Metab, 23: 712-724.
VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. Kivelä R, Bry M, Robciuc MR, Räsänen M, Taavitsainen M, Silvola JM, Saraste A, Hulmi JJ, Anisimov A, Mäyränpää MI, Lindeman JH, Eklund L, Hellberg S, Hlushchuk R, Zhuang ZW, Simons M, Djonov V, Knuuti J, Mervaala E, Alitalo K. 2014, EMBO Mol Med 6: 307-321.
Emmi Helle, Clinical research fellow
Minna Ampuja, Postdoctoral researcher
Oiva Arvola, Postdoctoral researcher
Karthik Amudhala Hemanthakumar, PhD student
Nebeyu Gizaw Yosef, PhD student
Aino Poikonen, PhD student
Sabina Selenius, PhD student
Ilse Paetau, Lab manager
Kialiina Tonttila, Master student
Erik Tolvanen, Master student
Jacob Andersson, Medical student
Sami Myllykangas, Medical student
Aliisa Auvinen, medical student
Siiri Toropainen, Master student
Laura Antola, Master student
Tatjana Punger, Master student
Elviira Hyvönen, Medical student
Charlotte Gouret, Undergraduate student
Maxime Laird, Undergraduate student
Manon Gruchet, Undergraduate student
Kirsi Mattinen, Laboratory technician
Jenny and Antti Wihuri Foundation
Academy of Finland
Sigrid Jusélius Foundation
Finnish Cardiovascular Research Foundation
Finnish Cancer Foundation
Finnish Medical Foundation
Finnish Cultural Foundation
Finnish Diabetes Research Foundation
Diabetes Wellness Finland