Nerurkar, N. | Search bioRxiv

bioRxiv2023

A chemo-mechanical model of endoderm movements driving elongation of the amniote hindgut

While mechanical and biochemical descriptions of development are each essential, integration of upstream morphogenic cues with downstream tissue mechanics remains understudied in many contexts during vertebrate morphogenesis. A posterior gradient of Fibroblast Growth Factor (FGF) ligands generates a contractile force gradient in the definitive endoderm, driving collective cell movements to form the hindgut. Here, we developed a two-dimensional chemo-mechanical model to investigate how mechanical properties of the endoderm and transport properties of FGF coordinately regulate this process. We began by formulating a 2-D reaction-diffusion-advection model that describes the formation of an FGF protein gradient due to posterior displacement of cells transcribing unstable Fgf8 mRNA during axis elongation, coupled with translation, diffusion, and degradation of FGF protein. This was used together with experimental measurements of FGF activity in the chick endoderm to inform a continuum model of definitive endoderm as an active viscous fluid that generates contractile stresses in proportion to FGF concentration. The model replicated key aspects of hindgut morphogenesis, confirms that heterogeneous - but isotropic - contraction is sufficient to generate large anisotropic cell movements, and provides new insight into how chemomechanical coupling across the mesoderm and endoderm coordinates hindgut elongation with outgrowth of the tailbud. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/541363v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@abb6fborg.highwire.dtl.DTLVardef@17a297eorg.highwire.dtl.DTLVardef@13a454borg.highwire.dtl.DTLVardef@9b699d_HPS_FORMAT_FIGEXP M_FIG C_FIG Summary statementThis study employs a mathematical model to investigate the interplay between morphogen gradients and tissue mechanics in regulating the collective cell movements that drive hindgut morphogenesis in the chick embryo.

developmental biology↗

bioRxiv2021

Gene signatures and host-parasite interactions revealed by dual single-cell profiling of Plasmodium vivax liver infection

Malaria-causing P. vivax parasites can linger in the human liver for weeks to years, and then reactivate to cause recurrent blood-stage infection. While an important target for malaria eradication, little is known about the molecular features of the replicative and non-replicative states of intracellular P. vivax parasites, or the human host-cell responses to them. Here, we leverage a bioengineered human microliver platform to culture Thai clinical isolates of P. vivax in primary human hepatocytes and conduct transcriptional profiling of infected cultures. By coupling enrichment strategies with bulk and single-cell analyses, we captured both parasite and host transcripts in individual hepatocytes throughout the infection course. We defined host- and state-dependent transcriptional signatures and identified previously unappreciated populations of replicative and non-replicative parasites, sharing features with sexual transmissive forms. We found that infection suppresses transcription of key hepatocyte function genes, and that P. vivax elicits an innate immune response that can be manipulated to control infection. Our work provides an extendible framework and resource for understanding host-parasite interactions and reveals new insights into the biology of malaria dormancy and transmission.

microbiology↗