In vitro strategies for mimicking dynamic cell–ECM reciprocity in 3D culture models

Abstract

The extracellular microenvironment regulates cell decisions through the accurate presentation at the cell surface of a complex array of biochemical and biophysical signals that are mediated by the structure and composition of the extracellular matrix (ECM). On the one hand, the cells actively remodel the ECM, which on the other hand affects cell functions. This cell–ECM dynamic reciprocity is central in regulating and controlling morphogenetic and histogenetic processes. Misregulation within the extracellular space can cause aberrant bidirectional interactions between cells and ECM, resulting in dysfunctional tissues and pathological states. Therefore, tissue engineering approaches, aiming at reproducing organs and tissues in vitro, should realistically recapitulate the native cell–microenvironment crosstalk that is central for the correct functionality of tissue-engineered constructs. In this review, we will describe the most updated bioengineering approaches to recapitulate the native cell microenvironment and reproduce functional tissues and organs in vitro. We have highlighted the limitations of the use of exogenous scaffolds in recapitulating the regulatory/instructive and signal repository role of the native cell microenvironment. By contrast, strategies to reproduce human tissues and organs by inducing cells to synthetize their own ECM acting as a provisional scaffold to control and guide further tissue development and maturation hold the potential to allow the engineering of fully functional histologically competent three-dimensional (3D) tissues.

Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

“…For example, cell culture models, a popular backbone platform to many biomedical research fields, are often two-dimensional and lack the ability to generate a mature, three-dimensional ECM similar to that found in natural tissues [ 7 , 96 , 97 ]. Because of limitations to existing models, widespread efforts are being made to develop novel three-dimensional strategies, incorporating a more physiologically relevant ECM [ 97 , 98 , 99 ]. With the generation of new model platforms, cost and throughput may be a more limiting factor.…”

Bioprinting of human dermal microtissues precursors as building blocks for endogenous in vitro connective tissue manufacturing

“…FI reached a value of almost 100% by day 8 (µTPs cohesion and fusion), with a contact of 180 • and a neck length of 1 mm. The fusion of µTPs was facilitated by the immature nature of the ECM produced within the µTPs during their maturation stage, which enabled not only cell/cell and cell/ECM adhesion, but also cells and ECM molecules migration when in contact between each other's, until completely being assembled forming a continuum of connective tissue [46]. Compared to previous work, whose focus was often confined to the study of short time cell/cell adhesion between microunits (cell sheets or spheroids), the herein reported cohesion and fusion process between µTPs, over a longer-term culture time, resembled more faithfully the native tissue repair and regeneration process [3,20,47].…”

Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis

“…For example, cell culture models, a popular backbone platform to many biomedical research fields, are often two-dimensional and lack the ability to generate a mature, three-dimensional ECM similar to that found in natural tissues [97][98][99]. Because of limitations to existing models, widespread efforts are being made to develop novel three-dimensional strategies incorporating more physiologically relevant ECM [98,100,101]. With the generation of new model platforms, cost and throughput may be a more limiting factor.…”