Biology subjects

Menendez, L.

Publications and source records attributed to Menendez, L..

3 recordsLinked to original sources

bioRxiv2025

Intrinsic Phenotypic Differences, Not Hemodynamic Shear, Associate with Cusp-Specific Remodeling in Aortic Valve Disease

Aortic valve disease (AVD) is asymmetric. Various clinical reports indicate that the non- coronary cusp (NCC) is disproportionally burdened by pathological remodeling like inflammation, fibrosis, and calcification. This has long been attributed to the resulting differences in hemodynamic load that arise from the presence, or lack thereof, of coronary ostia in respective sinuses. However, there is little to no empirical evidence to suggest that these differences in hemodynamic shear alone are enough to drive the difference in pathological remodeling that is observed. C57BL/6J mice exhibit a high variance in right coronary ostium (RCO) positioning with respect to the right coronary cusp (RCC). Through computational fluid dynamics (CFD) simulations of a mouse aortic valve (AoV) during end diastolic loading, we show negligible differences in wall shear stress (WSS) between a high RCO on the RCC and no ostium on the NCC. Also, though CFD analyses depict at least an order of magnitude difference in WSS through physiologically relevant ostia positions within the sinuses, ostium position does not correlate with calcification burden in a CKD mouse model of calcific AVD. Cusp dependent extracellular matrix (ECM) abundance analysis reveals asymmetric collagen and elastin content in healthy adult mice, but this does not follow the same trend as pathological remodeling. Instead, asymmetric abundance of elastin (P=0.034) and collagen (P=0.018) was mainly driven by an increase of these ECM proteins in the left coronary cusp (LCC) with no differences in leaflet thickness. Cusp dependent transcriptomic (spatial and bulk RNA sequencing) analyses reveal asymmetric phenotypic profiles between the three cusps in healthy adult mice. Of note, genes associated with vascular smooth muscle cell contraction and known modulators of AoV remodeling were upregulated in the NCC and downregulated in both the RCC and LCC. Together, these data suggest that the differences in shear resulting from the coronary ostia are not sufficient to explain the asymmetric onset of calcific AVD.

physiology↗

bioRxiv2025

Inducible, virus-free direct lineage reprogramming enhances scalable generation of human inner ear hair cell-like cells

Mammalian inner ear sensory hair cells are highly sensitive to environmental stress and do not regenerate, making hearing loss progressive and permanent. The paucity and extreme inaccessibility of these cells hinder the development of regenerative and otoprotective strategies, Direct lineage reprogramming to generate large quantities of hair cell-like cells in vitro offers a promising approach to overcome these experimental bottlenecks. Previously, we identified four transcription factors--Six1, Atoh1, Pou4f3, and Gfi1 (SAPG)--capable of converting mouse embryonic fibroblasts, adult tail tip fibroblasts, and postnatal mouse supporting cells into induced hair cell-like cells through retroviral or lentiviral transduction (Menendez et al., 2020). Here, we developed a virus-free, inducible system using a stable human induced pluripotent stem (iPS) cell line carrying doxycycline-inducible SAPG. Our inducible system significantly increases reprogramming efficiency compared to retroviral methods, achieving a [~]19-fold greater conversion to a hair cell fate in half the time. Immunostaining, Western blot, and single-nucleus RNA-seq analyses confirm the expression of hair cell-specific markers and activation of hair cell gene networks in reprogrammed cells. The reprogrammed hair cells closely resemble developing fetal hair cells, as evidenced by comparison with a human fetal inner ear dataset. Electrophysiological analysis reveals that the induced hair cell-like cells exhibit diverse voltage-dependent ion currents, including robust, quick-activating, slowly inactivating currents characteristic of primary hair cells. This virus-free approach improves scalability, reproducibility, and the modeling of hair cell differentiation, offering significant potential for hair cell regenerative strategies and preclinical drug discovery targeting ototoxicity and otoprotection.

developmental biology↗

bioRxiv2018

Out of Africa by spontaneous migration waves

Hominin evolution is characterized by progressive regional differentiation, as well as migration waves, leading to anatomically modern humans that are assumed to have emerged in Africa and spread over the whole world. Why or whether Africa was the source region of modern humans and what caused their spread remains subject of ongoing debate. We present a spatially explicit, stochastic numerical model that includes ongoing mutations, demic diffusion, assortative mating and migration waves. Diffusion and assortative mating alone result in a structured population with relatively homogeneous regions bound by sharp clines. The addition of migration waves results in a power-law distribution of wave areas: for every large wave, many more small waves are expected to occur. This suggests that one or more out-of-Africa migrations would probably have been accompanied by numerous smaller migration waves across the world. The migration waves are considered \"spontaneous\", as the current model excludes environmental or other factors. Large waves preferentially emanate from the central areas of large, compact inhabited areas. During the Pleistocene, Africa was the largest such area most of the time, making Africa the statistically most likely origin of anatomically modern humans, without a need to invoke additional environmental or ecological drivers.

evolutionary biology↗