TABLA DE VALORACIÓN INTEGRAL DE LA CARRERA INDICADORES

biologists and the field of stem cell biology because embryonic mechanisms occur through biochemical activity in controlled physical environments [157]. On the one hand, developmental biology studies processes by which cells and tissues, originating from the

embryo, evolve towards adult function. These processes are complex, strictly controlled in time and space and, most notably, conserved across multiple species as a result of evolution. In other words, the role of developmental biology is to identify physiological factors directing biochemical responses that control embryonic mechanisms. On the other hand, the role of tissue mechanics is both to determine how forces modulate the physical context in which physiological factors perform biological functions, and also to actuate those forces. These two types of mechanisms, biochemical signaling and tissue mechanics, act in coordination at all stages of development – including the developing embryo – and determine how tissues mature and acquire specialized function.

We can use lineage specification processes in strategies for tissue regeneration in adult organs if we understand the mechanisms underlying differentiation control, including mechanotransduction, from the onset of development and throughout their homeostatic control in postnatal function and disease. In order to analyze lineage specification under a mechanotransduction viewpoint, we first need to recognize that cells, including embryonic stem cells, are mechanically sensitive in all stages of development because they possess mechanosensitive organelles such as primary cilia and gated ionic channels [218]. In the blastocyst, nodal cilia produce asymmetric flow across the ventral node, which is responsible for establishing left-right asymmetry during early body plan establishment. Other non-motile primary cilia localize along the paths of the nodal flow and sense it, which results in differential expression patterns of early morphogens from, among others, the Hh signaling pathway [219]. All these events lead to lineage specification mechanisms poorly understood under mechanical terms. Therefore, we need to outline differentiation principles within mechanical frameworks in order to understand maturation mechanisms in terms of tissue

mechanics. This is especially pressing for endodermal tissues, whose function is not traditionally interpreted in terms of mechanical action.

Research on embryonic tissue mechanics advances in parallel with the advent of technologies able to test at appropriate scales of cellular and tissue function. Research on tissue mechanics of embryos and stem cells has revealed, for example, that differentiation is a stiffness-dependent mechanism [47] accompanied by loss of mechanical compliance in cells [196], and that embryos exhibit phase ordering that parallels behavior in liquid mixtures [159, 160, 176-178, 190, 197, 198]. Differentiation patterns during embryonic development arise, in part, from induction of active flow by mechanical organelles like cilia [219]. In addition, we also know tissue formation and maintenance depends on controlled mechanisms of interstitial flow throughout life [179].

In the recent past, research on human developmental biomechanics had limited access to embryonic tissues. In fact, most developmental biology research has been performed in model species, which includes non-mammalian species (e.g zebrafish) and invertebrates (e.g. roundworm C. elegans). Induced pluripotent stem (iPS) cells provide an alternate source for human embryonic-like cells that can be used to advance this type of research. Since their invention, iPS cells have redefined our understanding of differentiation as a unidirectional process by showing, for example, that a handful of genes suffice to reconstitute pluripotency in somatic cells. This process, usually performed in human foreskin fibroblasts and also possible with other primary cells, consists of retroviral transfection of Oct3/4, Sox2 and either Nanog and Lin28 [220] or c-Myc and Klf4. The current belief is that transfecting these genes in somatic cells induces pluripotency because they participate in global demethylation of the chromatin, which propels the genome into a pluripotent de-

differentiated state. Transfected somatic cells, when fully developed into iPS cells, exhibit trademark characteristics of ES cells such as teratoma formation, asymmetric division and differentiation into all germlines [221]. These characteristics help developmental biologists because iPS cells are more accessible than ES cells as experimental models.

Although many of the biochemical mechanisms in ES and iPS cells match with remarkable precision, there are some differences between them. First of all, iPS cells originate from retroviral transfection of pluripotency genes, thus inducing genomic alterations in iPS cells that ES cells do not share. In addition, homogeneity within iPS populations depends not only on successful transfection of all pluripotency genes in all cells, but also on cells successfully rescuing a functional pluripotent state beyond gene expression. Therefore, variations in pluripotency potential of iPS cells indicate that the process requires further optimization, including improved iPS cell isolation in terms of functional requirements like EpCAM and E-cadherin expression, and shows that degrees of global demethylation could vary across iPS cell preparations [161]. In comparison, cells from a single ES cell source are defined by their homogeneous pluripotency and equivalent genomic characteristics [221].

As long as we recognize functional differences between iPS cells and ES cells a priori, the iPS model can enhance our understanding of embryonic development with respect to mechanotransduction. To our knowledge, there is only a handful of electrophysiological studies on iPS cell function that explicitly search for differences in mechanical and physiological mechanisms between ES cells and iPS cells. Those studies found only minimal distinctions in electrophysiological activity [222, 223]. For that reason alone, and without further evidence, we can only assume that iPS cells model ES cell responses to mechanical

stimuli that replicate mechanotransduction mechanisms in embryonic stages with acceptable homology.

8.3. ALTERNATIVE MECHANOTRANSDUCTION AMPLIFICATION SYSTEMS