to organogenesis of the kidney [8] and the heart [5, 9, 10] as
clusters of mesenchymal cells migrate great distances in the embryo
and transition to epithelial phenotypes to form the simple tubule of
the developing kidney or a disk of the heart primordia. The timing
and progression of MET during development parallels the events
leading to the formation of secondary metastases [11] and suggest
these processes share common regulatory mechanisms [12].
Despite the significance of MET in topics ranging from cell
biology to human health, little is known about the spatiotemporal
dynamics of MET progression or how the physical regulation of
MET integrates with conventional intracellular molecular signaling
pathways [13]. The limited understanding of the cellular and
molecular mechanisms of MET directly results from both the
inherent unpredictability of MET emergence deep within multiple
layers of cells in vivo and a lack of a tractable 3D model system that
can recapitulate the full process of MET. By contrast, the past
decade of research has provided great insight into the regulatory
mechanisms of EMT due to established in vitro and animal models
that permit profiling differential gene expression, tracing cellular
transitions, and manipulating signaling factors [14, 15]. MET is
often viewed as the reverse of EMT; however, the complex sequential progression of MET may not be reversed by reintroduction of
mesenchymal inducing factors alone [16]. These gaps in our understanding of MET indicate a clear demand for a model system that
can be used to explore the full progression by which mesenchymal
cells initiate and progressively adopt apicobasal polarity, propagate
“epithelialness” and stabilize the new architecture of the
epithelium [13].
The physical mechanics of the microenvironment changes prior
to and concomitant with MET, as dispersed migratory mesenchymal cells first cluster then spontaneously develop cell–cell adhesions. As MET progresses, transitioning tissues often form
compact spherical aggregates, disks, or cords. Mechanical tension,
driven by cortical actin contraction and cell–cell adhesion, is known
to shape cells and tissues during aggregation in vivo [17] and
in vitro [18, 19] and has been implicated in other aspects of tissue
self-assembly [20], cell rearrangement [21, 22], and cell fate determination [23]. To understand the role of tension in these processes,
numerous methods for measuring tension sensed by cells have
emerged [24, 25], including FRET-based tension sensors [26] on
load-bearing proteins such as cadherin [27], vinculin [28, 29], and
talin [30, 31]. Quantitative measures of tension may be complemented by qualitative indicators such as nuclear translocation of
YAP [32], an endogenous mechanosensor, that can be used as a
proxy to assess tension experienced by a cell. Combining quantitative biomechanical analysis with qualitative tension sensors and
molecular genetic approaches can expose the relationship between
tension and MET.
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Hye Young Kim and Lance A. Davidson
clusters of mesenchymal cells migrate great distances in the embryo
and transition to epithelial phenotypes to form the simple tubule of
the developing kidney or a disk of the heart primordia. The timing
and progression of MET during development parallels the events
leading to the formation of secondary metastases [11] and suggest
these processes share common regulatory mechanisms [12].
Despite the significance of MET in topics ranging from cell
biology to human health, little is known about the spatiotemporal
dynamics of MET progression or how the physical regulation of
MET integrates with conventional intracellular molecular signaling
pathways [13]. The limited understanding of the cellular and
molecular mechanisms of MET directly results from both the
inherent unpredictability of MET emergence deep within multiple
layers of cells in vivo and a lack of a tractable 3D model system that
can recapitulate the full process of MET. By contrast, the past
decade of research has provided great insight into the regulatory
mechanisms of EMT due to established in vitro and animal models
that permit profiling differential gene expression, tracing cellular
transitions, and manipulating signaling factors [14, 15]. MET is
often viewed as the reverse of EMT; however, the complex sequential progression of MET may not be reversed by reintroduction of
mesenchymal inducing factors alone [16]. These gaps in our understanding of MET indicate a clear demand for a model system that
can be used to explore the full progression by which mesenchymal
cells initiate and progressively adopt apicobasal polarity, propagate
“epithelialness” and stabilize the new architecture of the
epithelium [13].
The physical mechanics of the microenvironment changes prior
to and concomitant with MET, as dispersed migratory mesenchymal cells first cluster then spontaneously develop cell–cell adhesions. As MET progresses, transitioning tissues often form
compact spherical aggregates, disks, or cords. Mechanical tension,
driven by cortical actin contraction and cell–cell adhesion, is known
to shape cells and tissues during aggregation in vivo [17] and
in vitro [18, 19] and has been implicated in other aspects of tissue
self-assembly [20], cell rearrangement [21, 22], and cell fate determination [23]. To understand the role of tension in these processes,
numerous methods for measuring tension sensed by cells have
emerged [24, 25], including FRET-based tension sensors [26] on
load-bearing proteins such as cadherin [27], vinculin [28, 29], and
talin [30, 31]. Quantitative measures of tension may be complemented by qualitative indicators such as nuclear translocation of
YAP [32], an endogenous mechanosensor, that can be used as a
proxy to assess tension experienced by a cell. Combining quantitative biomechanical analysis with qualitative tension sensors and
molecular genetic approaches can expose the relationship between
tension and MET.
276
Hye Young Kim and Lance A. Davidson