Cardiac Regeneration
Professor Nadia Rosenthal, Head of Group
Our laboratory focuses on regenerative biology, a rapidly growing branch of science that explores the mechanisms employed by different organisms to replace lost or damaged tissues and organs. The regeneration of organs and appendages after injury occurs in diverse animal species but appears to be a remote and exceptional attribute in mammalian organs. One of the major problems in mammalian tissue regeneration is the paucity of damaged tissue to support cell survival and proliferation. Inflammatory responses leading to fibrous tissue formation and production of oxidative stress species generate a non-permissive environment for cell migration and proliferation/differentiation, reducing the possibility of stem cell progenitors, as well as circulating stem cells, to properly benefit the injured organ. Mammalian cardiac tissue has a particularly limited regenerative capacity1. Reversal of cardiac damage entails generation of new contractile myocytes and formation of a capillary network able to support the greater demands of the new regenerating myocardium.
Enhanced cardiac repair in mIGF-1 transgenic mice after myocardial infarct (Click to enlarge)
Our recent analyses of a local IGF-1 isoform (mIGF-1) overexpressed in the heart showed induction of new signalling pathways and complete cardiac repair within four weeks after myocardial infarction with minimal scar formation and lowered inflammatory response2. Since supplementary mIGF-1 expression does not alter normal heart development or long-term postnatal cardiac growth and function, these studies suggest new avenues for promoting the enhancement of cardiac regeneration, and have prompted us to pursue clinically feasible therapeutic strategies.
Modes of cardiac regeneration by stem cells and growth factor (Click to enlarge)
We are evaluating the efficiency and efficacy of a combinatorial cell/growth factor therapy in cardiac regeneration, using mouse embryonic stem cells (ESC) since they present a clear advantage in myocardial reconstitution, maintaining the necessary pluripotent genetic programming to adopt the cardiomyocyte phenotype, and a lentiviral vector carrying mIGF-1 under the control of the tetracycline operon system to allow its induction at will. Our purpose is to analyse the in vivo treatment of cardiac infarct by cell-based delivery of mIGF-1.
We are also characterising key cellular players in the mIGF-1 regenerative response, concentrating on the role of serum glucocorticoid kinase 1 and 3 and thymosin beta 4. We are designing knockout and knockdown technologies of both molecules by using the Cre/Lox system to dissect their contribution to cardiac repair and re-vascularization as well as to cardiac development in mice overexpressing mIGF-1.
Model of mIGF-1-mediated neovascularization and tissue restoration induced by specific monocyte/macrophage subsets
In addition, we have observed that the signalling activated by mIGF-1 may lead to tissue revascularization and anti-inflammatory response after myocardial infarct through the recruitment of a subset of monocytes and/or macrophages3. We are, therefore, investigating the origin and identity of specific monocyte/macrophage subsets, determining whether myocardial regeneration induced by mIGF-1 is mediated by stimulating bone marrow- and/ or spleen-derived monocytic cells to form new vessels, and analysing the efficiency of the different monocytic cell population from above to reconstitute myocardial vessels and/or elicit anti-inflammatory response in vivo in a cell-based therapy.
We have recently become involved in the study of the role of members of the Follistatin family in heart failure and recovery. Follistatins are potent inhibitors of activin signalling with roles in diverse biological processes including cell proliferation, wound healing, inflammation and skeletal muscle growth. We recently described that the expression of Follistatin-like 1 and follistatin-like 3 (Fstl1 and Fstl3) is elevated in patients with heart failure and returns to normal levels following recovery4. However, their role in heart failure is largely unknown. Together with Dr. Paul JR Barton we have started a research project which aims to study the function of these proteins in both heart failure and recovery by using a combination of knockout and over-expressing transgenic mice.
Collectively, these studies explore the feasibility of recapturing regenerative capacity by identifying and modulating key signalling pathways that induce the recruitment of circulating progenitor cells to sites of tissue damage and augment local repair mechanisms.
Selected Publications
Santini MP, Winn N, Rosenthal N. Signalling pathways in cardiac regeneration. Novartis Found Symp. 2006;274:228-38.
Santini MP, Tsao L, Monassier L, Theodoropoulos C, Carter J, Lara-Pezzi E, Slonimsky E, Salimova E, Delafontaine P, Song YH, Bergmann M, Freund C, Suzuki K, Rosenthal N. Enhancing repair of the mammalian heart. Circ Res. 2007;100(12):1732-40.
Daniela Ruffell, Foteini Mourkioti, Adriana Gambardella, Peggy Kirstetter, Rodolphe G. Lopez, Nadia Rosenthal, and Claus Nerlov. A CREB-C/EBP cascade induces M2 macrophage specific gene expression and promotes muscle injury repair. PNAS 2009; 106: 17475-17481
Lara-Pezzi E, Felkin LE, Birks EJ, Sarathchandra P, Panse KD, George R, Hall JL, Yacoub MH, Rosenthal N, Barton PJ. Expression of follistatin-related genes is altered in heart failure. Endocrinology. 2008;149(11):5822-7.
Nadia Rosenthal, Nadine Winn and Maria Paola Santini. IGF-1, muscle progenitors and heart failure. Cardiovascular Regeneration and Stem Cell Therapy, edited by Annarosa Leri, Piero Anversa and William Frishman. Blackwell Publishing, Part III chapter 15: 149-158, 2007.
