Biology subjects

Bensimon-Brito, A.

Publications and source records attributed to Bensimon-Brito, A..

5 recordsLinked to original sources

bioRxiv2022

Fin ray branching is defined by TRAP+ osteolytic tubules

The shaping of bone structures relies on various cell types and signalling pathways. Here, we use the zebrafish bifurcating fin rays during regeneration to investigate bone patterning. We found that the regenerating fin rays form via two mineralization fronts that undergo an osteoblast-dependent fusion/stitching until the branchpoint, and that bifurcation is not simply the splitting of one unit into two. We identified tartrate-resistant acid phosphatase-positive (TRAP+) osteolytic tubular structures at the branchpoints, here named osteolytic tubules (OLTs). Chemical inhibition of their bone-resorbing activity strongly impairs ray bifurcation, indicating that OLTs counteract the stitching process. Finally, by testing different osteoactive compounds, we show that the position of the branchpoint depends on the balance between bone mineralization and resorption activities. Overall, these findings provide a new perspective on fin ray formation and bifurcation, and reveal a key role for OLTs in defining the proximo-distal position of the branchpoint. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/491182v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@7d0b9dorg.highwire.dtl.DTLVardef@1859078org.highwire.dtl.DTLVardef@1cfb816org.highwire.dtl.DTLVardef@3ec7f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Zebrafish caudal fin amputation induces a metabolic switch necessary for cell identity transitions and cell cycle re-entry to support blastema formation and bone regeneration

Regeneration depends on the ability of mature cells at the injury site to respond to injury, generating tissue-specific progenitors that incorporate the blastema and proliferate to reconstitute the original organ architecture. The metabolic microenvironment has been tightly connected to cell function and identity during development and tumorigenesis. Yet, the link between metabolism and cell identity at the mechanistic level in a regenerative context remains unclear. The adult zebrafish caudal fin, and bone cells specifically, have been crucial for the understanding of mature cell contribution to tissue regeneration. Here, we use this model to explore the relevance of glucose metabolism for the cell fate transitions preceding new osteoblast formation and blastema assembly. We show that injury triggers a shift in the metabolic profile at early stages of regeneration, enhancing glycolysis at the expense of mitochondrial oxidation. This metabolic switch mediates transcriptional changes that make mature osteoblast amenable to be reprogramed into pre-osteoblasts and induces cell cycle re-entry and progression. Manipulation of the metabolic profile led to severe reduction of the pre-osteoblast pool, diminishing their capacity to generate new osteoblasts, and to a complete abrogation of blastema formation. Overall, our data indicate that metabolic alterations have a powerful instructive role in regulating genetic programs that dictate fate decisions and stimulate proliferation, thereby providing a deeper understanding on the mechanisms regulating blastema formation and bone regeneration.

developmental biology↗

bioRxiv2020

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

Mammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Using alk5a/tgfbr1a mutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.

developmental biology↗

bioRxiv2020

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which have often been associated with impaired TGF-{beta} signaling. To further investigate the role of TGF-{beta} signaling in OFT formation, we generated zebrafish lacking the type I TGF-{beta} receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-{beta} target, partially restores OFT morphology and function. These findings reveal a new requirement for endothelial TGF-{beta} signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.

developmental biology↗

bioRxiv2019

Cardiac valve regeneration in adult zebrafish: importance of TGF-β signaling in new tissue formation

Cardiac valve disease can lead to severe cardiac dysfunction and is thus a frequent cause of morbidity and mortality. Its main treatment is valve replacement, which is currently greatly limited by the poor recellularization and tissue formation potential of the implanted valves. As we still lack suitable animal models to identify modulators of these processes, here we used the adult zebrafish and found that, upon valve decellularization, they initiate a striking regenerative program that leads to the formation of new functional valves. After injury, endothelial and kidney marrow-derived cells undergo cell cycle re-entry and differentiate into new extracellular matrix-secreting valve cells. The Transforming Growth Factor beta (TGF{beta}) signaling pathway promotes this process by enhancing progenitor cell proliferation as well as valve cell differentiation. These findings reveal a key role for TGF{beta} signaling in valve regeneration and also establish the zebrafish as a model to identify and test factors promoting valve recellularization and growth.

developmental biology↗