Elastogenesis at the onset of human cardiac valve development

Abstract

Semilunar valve leaflets have a well-described trilaminar histoarchitecture, with a sophisticated elastic fiber network. It was previously proposed that elastin-containing fibers play a subordinate role in early human cardiac valve development; however, this assumption was based on data obtained from mouse models and human second and third trimester tissues. Here, we systematically analyzed tissues from human fetal first (4-12 weeks) and second (13-18 weeks) trimester, adolescent (14-19 years) and adult (50-55 years) hearts to monitor the temporal and spatial distribution of elastic fibers, focusing on semilunar valves. Global expression analyses revealed that the transcription of genes essential for elastic fiber formation starts early within the first trimester. These data were confirmed by quantitative PCR and immunohistochemistry employing antibodies that recognize fibronectin, fibrillin 1, 2 and 3, EMILIN1 and fibulin 4 and 5, which were all expressed at the onset of cardiac cushion formation (~week 4 of development). Tropoelastin/elastin protein expression was first detectable in leaflets of 7-week hearts. We revealed that immature elastic fibers are organized in early human cardiovascular development and that mature elastin-containing fibers first evolve in semilunar valves when blood pressure and heartbeat accelerate. Our findings provide a conceptual framework with the potential to offer novel insights into human cardiac valve development and disease.

Generation and Assessment of Functional Biomaterial Scaffolds for Applications in Cardiovascular Tissue Engineering and Regenerative Medicine

“…To enable the process of elastogenesis, further proteins such as fibulins, elastin microfibril interface located protein 1 (EMILIN‐1), fibronectin, latent TGF‐beta binding protein 4 (LTBP‐4) are necessary . The process of elastogenesis is highly complex and still not completely understood; however, it has been shown that these events already play a major role in early human cardiovascular development . Therefore, when aiming for a nature‐mimicking highly functional biomaterial scaffold, elastic fibers and the elastic fiber‐associated proteins must be considered.…”

3D mapping reveals a complex and transient interstitial matrix during murine renal development

“…Interestingly, several interstitial matrix proteins (COL5A2, COL12A1, COL26A1, EMID1, FBN1, FBLN5, ELN, THSD4) were significantly elevated or exclusively found at the perinatal timepoints, including components of the elastin-microfibril axis. [39][40][41] Overall, there was a significant decrease in interstitial matrix and a significant increase in basement membrane proteins over development ( Figure 4A). For example, the basement membrane proteins LAMA5 and NID1 were significantly increased at P3 compared to E14.5…”

“…The perinatal increase in abundance of these collagens and elastinmicrofibril axis proteins may provide mechanical integrity by transiently stabilizing the 3D fibrous medullary ray sheath and vertical fibers ( Figures 5, 7, 8). Interestingly, proteins in the elastinmicrofibril axis (EMILIN1, EMILIN3, FBN1, FBN2, FBN3, and THSD4) [39][40][41] were also elevated in human fetal kidneys compared with the adult, 12 indicating this understudied axis in the kidney warrants further research. 40,41 In contrast with the fibrous structures observed at perinatal timepoints, relatively little interstitial patterning was observed in the adult using our decellularization method ( Figure S11).…”

Modulation of inflammation and angiogenesis and changes in ECM GAG-activity via dual delivery of nucleic acids

“…Heat-mediated antigen retrieval was performed in a pressurecooker in the appropriate buffers as previously described [42]. A secondary FITC-conjugated goat anti-rabbit IgG (1:250; A-11037, Life Technologies, Darmstadt, Germany) was used.…”