Extracellular Matrix Mechanical Properties and Regulation of the Intestinal Stem Cells: When Mechanics Control Fate

Abstract

Intestinal stem cells (ISC) are crucial players in colon epithelium physiology. The accurate control of their auto-renewal, proliferation and differentiation capacities provides a constant flow of regeneration, maintaining the epithelial intestinal barrier integrity. Under stress conditions, colon epithelium homeostasis in disrupted, evolving towards pathologies such as inflammatory bowel diseases or colorectal cancer. A specific environment, namely the ISC niche constituted by the surrounding mesenchymal stem cells, the factors they secrete and the extracellular matrix (ECM), tightly controls ISC homeostasis. Colon ECM exerts physical constraint on the enclosed stem cells through peculiar topography, stiffness and deformability. However, little is known on the molecular and cellular events involved in ECM regulation of the ISC phenotype and fate. To address this question, combining accurately reproduced colon ECM mechanical parameters to primary ISC cultures such as organoids is an appropriated approach. Here, we review colon ECM physical properties at physiological and pathological states and their bioengineered in vitro reproduction applications to ISC studies.

The Charming World of the Extracellular Matrix: A Dynamic and Protective Network of the Intestinal Wall

“…The intestinal mucosa is constantly subject to mechanical stimuli that can activate molecular signals on the epithelial cells and leads to alterations of the epithelium biology. Mainly two forms of mechanical forces act on the intestinal wall: contractile activities (i.e., peristalsis) and shear stress (due to the presence of food, gas, and fluids) (192,195,196). These forces heavily impact bowel morphogenesis.…”

“…An interesting study conducted on rat's small intestine revealed that ECM fibers are organized as two interwoven arrays running diagonally around the crypt wall: one set clockwise and the other one set counterclockwise and oriented at a range of angle ± 30-50 • (192,(195)(196)(197). This spatial arrangement provides mucosa with the right flexibility to fit stretch forces (192,(195)(196)(197). The ECM conveys this mechanical information to cells through an integrin network, activates focal adhesion kinase (FAK) and the extracellular signal-regulated kinase (ERK) signaling, finally leading to cell proliferation.…”

Mechanical Studies of the Third Dimension in Cancer: From 2D to 3D Model

“…As discussed, the matrix stiffness not only affects migration properties, cellular response to therapeutics, and cell fate [ 124 ] but also the phenotype of cancer cells. Decoupling matrix stiffness cues from other characteristics in cancer studies can be achieved utilizing engineered hydrogels, but we need to overcome technical issues in conventional mechanical characterization techniques, particularly at the length scale of individual cells.…”

Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?

“…Interestingly, αSMA staining also positively correlates with CRC development [ 100 ], indicating a continuous increase in the activated-fibroblast population. Matrix stiffness has a prominent role in the control of the physiological behavior of stem cells [ 101 ]. Indeed, culturing mesenchymal stem cells on soft or stiff substrates, it has been shown that stiffness by itself can drive the differentiation toward peculiar lineages and promotes cells proliferation [ 102 , 103 , 104 , 105 ].…”