Regulation and functions of cell division in the intestinal tissue.

In multicellular organisms, epithelial cells are key elements of tissue organization. In developing epithelial tissues, cellular proliferation and differentiation are under the tight regulation of morphogenetic programs to ensure correct organ formation and functioning. In these processes, proliferation rates and division orientation regulate the speed, timing and direction of tissue expansion but also its proper patterning. Moreover, tissue homeostasis relies on spatio-temporal modulations of daughter cell behavior and arrangement. These aspects are particularly crucial in the intestine, which is one of the most proliferative tissues in adults, making it a very attractive adult organ system to study the role of cell division on epithelial morphogenesis and organ function. Although epithelial cell division has been the subject of intense research for many years in multiple models, it still remains in its infancy in the context of the intestinal tissue. In this review, we focus on the current knowledge on cell division and regulatory mechanisms at play in the intestinal epithelial tissue, as well as their importance in developmental biology and physiopathology.

Integrin-based adhesion compartmentalizes ALK3 of the BMPRII to control cell adhesion and migration.

The spatial organization of cell-surface receptors is fundamental for the coordination of biological responses to physical and biochemical cues of the extracellular matrix. How serine/threonine kinase receptors, ALK3-BMPRII, cooperate with integrins upon BMP2 to drive cell migration is unknown. Whether the dynamics between integrins and BMP receptors intertwine in space and time to guide adhesive processes is yet to be elucidated. We found that BMP2 stimulation controls the spatial organization of BMPRs by segregating ALK3 from BMPRII into ß3 integrin-containing focal adhesions. The selective recruitment of ALK3 to focal adhesions requires ß3 integrin engagement and ALK3 activation. BMP2 controls the partitioning of immobilized ALK3 within and outside focal adhesions according to single-protein tracking and super-resolution imaging. The spatial control of ALK3 in focal adhesions by optogenetics indicates that ALK3 acts as an adhesive receptor by eliciting cell spreading required for cell migration. ALK3 segregation from BMPRII in integrin-based adhesions is a key aspect of the spatio-temporal control of BMPR signaling.

Differential bioactivity of four BMP-family members as function of biomaterial stiffness.

While a soft film itself is not able to induce cell spreading, BMP-2 presented via such soft film (so called "matrix-bound BMP-2") was previously shown to trigger cell spreading, migration and downstream BMP-2 signaling. Here, we used thin films of controlled stiffness presenting matrix-bound BMPs to study the effect of four BMP members (BMP-2, 4, 7, 9) on cell adhesion and differentiation of skeletal progenitors. We performed automated high-content screening of cellular responses, including cell number, cell spreading area, SMAD phosphorylation and alkaline phosphatase activity. We revealed that the cell response to bBMPs is BMP-type specific, and involved certain BMP receptors and beta chain integrins. In addition, this response is stiffness-dependent for several receptors. The basolateral presentation of the BMPs allowed us to discriminate the specificity of cellular response, especiallyd the role of type I and II BMP receptors and of ß integrins in a BMP-type and stiffness-dependent manner. Notably, BMP-2 and BMP-4 were found to have distinct roles, while ALK5, previously known as a TGF-ß receptor was revealed to be involved in the BMP-pathway.

Learning from BMPs and their biophysical extracellular matrix microenvironment for biomaterial design.

It is nowadays well-accepted that the extracellular matrix (ECM) is not a simple reservoir for growth factors but is an organization center of their biological activity. In this review, we focus on the ability of the ECM to regulate the biological activity of BMPs. In particular, we survey the role of the ECM components, notably the glycosaminoglycans and fibrillary ECM proteins, which can be promoters or repressors of the biological activities mediated by the BMPs. We examine how a process called mechano-transduction induced by the ECM can affect BMP signaling, including BMP internalization by the cells. We also focus on the spatio-temporal regulation of the BMPs, including their release from the ECM, which enables to modulate their spatial localization as well as their local concentration. We highlight how biomaterials can recapitulate some aspects of the BMPs/ECM interactions and help to answer fundamental questions to reveal previously unknown molecular mechanisms. Finally, the design of new biomaterials inspired by the ECM to better present BMPs is discussed, and their use for a more efficient bone regeneration in vivo is also highlighted.