All tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The... Show moreAll tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The extracellular matrix (ECM) of endothelial cells, also known as the perivascular matrix, forms an organ specific vascular niche that orchestrates mechano-, growth factor, and angiocrine signaling required for tissue homeostasis and organ repair. This concise review describes how this perivascular ECM functions as a signaling platform and how this knowledge can impact the field of regenerative medicine, for example, when designing artificial matrices or using decellularized scaffolds from organs. Stem Cells Translational Medicine 2019;8:375-382 Show less
Witjas, F.M.R.; Berg, B.M. van den; Berg, C.W. van den; Engelse, M.A.; Rabelink, T.J. 2018
All tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The... Show moreAll tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The extracellular matrix (ECM) of endothelial cells, also known as the perivascular matrix, forms an organ specific vascular niche that orchestrates mechano-, growth factor, and angiocrine signaling required for tissue homeostasis and organ repair. This concise review describes how this perivascular ECM functions as a signaling platform and how this knowledge can impact the field of regenerative medicine, for example, when designing artificial matrices or using decellularized scaffolds from organs. Show less
Berg, C.W. van den; Ritsma, L.; Avramut, M.C.; Wiersma, L.E.; Berg, B.M. van den; Leuning, D.G.; ... ; Rabelink, T.J. 2018
The research described in this thesis focuses on the use of both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to understand cardiac lineage development and disease. To... Show moreThe research described in this thesis focuses on the use of both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to understand cardiac lineage development and disease. To investigate the possibility of studying inherited cardiac diseases, we compared pluripotent stem cell-derived cardiomyocytes by investigating both a mouse and human model of a complex cardiac overlap syndrome caused by a mutation in the gene SCN5A. We demonstrated that both ESC- and iPSC-derived cardiomyocytes can recapitulate the characteristics of the disease. Furthermore this thesis describes a detailed protocol to differentiate human pluripotent stem cells to cardiomyocytes that was applied in the study comparing hESC- and hiPSC- derived cardiomyocytes at several time points during cardiac differentiation. We targeted fluorescent marker GFP to one allele of NKX2-5 in a human iPSC line that now matched a similar human ESC reporter line previously generated in the laboratory. This offered the opportunity to obtain cardiomyocytes and their precursors at different time points during the differentiation and determine the true degree of similarity between both pluripotent stem cell sources. Additionally the same hESC- and hiPSC-derived cardiomyocytes were compared to a unique set of foetal heart samples. Show less
Berg, C.W. van den; Okawa, S.; Lopes, S.M.C.D.; Iperen, L. van; Passier, R.; Braam, S.R.; ... ; Mummery, C.L. 2015
BACKGROUND Pluripotent stem cells (PSCs) offer a new paradigm for modeling genetic cardiac diseases, but it is unclear whether mouse and human PSCs can truly model both gain- and loss-of-function... Show moreBACKGROUND Pluripotent stem cells (PSCs) offer a new paradigm for modeling genetic cardiac diseases, but it is unclear whether mouse and human PSCs can truly model both gain- and loss-of-function genetic disorders affecting the Na(+) current (I(Na)) because of the immaturity of the PSC-derived cardiomyocytes. To address this issue, we generated multiple PSC lines containing a Na(+) channel mutation causing a cardiac Na(+) channel overlap syndrome. METHOD AND RESULTS Induced PSC (iPSC) lines were generated from mice carrying the Scn5a(1798insD/+) (Scn5a-het) mutation. These mouse iPSCs, along with wild-type mouse iPSCs, were compared with the targeted mouse embryonic stem cell line used to generate the mutant mice and with the wild-type mouse embryonic stem cell line. Patch-clamp experiments showed that the Scn5a-het cardiomyocytes had a significant decrease in I(Na) density and a larger persistent I(Na) compared with Scn5a-wt cardiomyocytes. Action potential measurements showed a reduced upstroke velocity and longer action potential duration in Scn5a-het myocytes. These characteristics recapitulated findings from primary cardiomyocytes isolated directly from adult Scn5a-het mice. Finally, iPSCs were generated from a patient with the equivalent SCN5A(1795insD/+) mutation. Patch-clamp measurements on the derivative cardiomyocytes revealed changes similar to those in the mouse PSC-derived cardiomyocytes. CONCLUSION Here, we demonstrate that both embryonic stem cell- and iPSC-derived cardiomyocytes can recapitulate the characteristics of a combined gain- and loss-of-function Na(+) channel mutation and that the electrophysiological immaturity of PSC-derived cardiomyocytes does not preclude their use as an accurate model for cardiac Na(+) channel disease. Show less
Recent advances in pluripotent stem cell biology now make it possible to generate human cardiomyocytes in vitro from both healthy individuals and from patients with cardiac abnormalities. This... Show moreRecent advances in pluripotent stem cell biology now make it possible to generate human cardiomyocytes in vitro from both healthy individuals and from patients with cardiac abnormalities. This offers unprecedented opportunities to study cardiac disease development 'in a dish' and establish novel platforms for drug discovery, either to prevent disease progression or to reverse it. In this review paper, we discuss some of the genetic diseases that affect the heart and illustrate how these new paradigms could assist our understanding of cardiac pathogenesis and aid in drug discovery. In particular, we highlight the limitations of other commonly used model systems in predicting the consequences of drug exposure on the human heart. Show less
Recent advances in pluripotent stem cell biology now make it possible to generate human cardiomyocytes in vitro from both healthy individuals and from patients with cardiac abnormalities. This... Show moreRecent advances in pluripotent stem cell biology now make it possible to generate human cardiomyocytes in vitro from both healthy individuals and from patients with cardiac abnormalities. This offers unprecedented opportunities to study cardiac disease development 'in a dish' and establish novel platforms for drug discovery, either to prevent disease progression or to reverse it. In this review paper, we discuss some of the genetic diseases that affect the heart and illustrate how these new paradigms could assist our understanding of cardiac pathogenesis and aid in drug discovery. In particular, we highlight the limitations of other commonly used model systems in predicting the consequences of drug exposure on the human heart. Show less
