IMR Press / FBL / Volume 24 / Issue 3 / DOI: 10.2741/4728
Open Access Review
Polarity as a physiological modulator of cell function
Show Less
1 Biomedical Engineering Program, University of South Carolina, 301 Main St, Columbia, SC 29208
2 Department of Chemical Engineering, University of South Carolina,301 Main St, Columbia SC 29208
Send correspondence to: Ehsan Jabbarzadeh, University of South Carolina 301 Main St Columbia, SC 29208, Tel: 803-777-3297, Fax: 803-777-8265, E-mail: ehsan@sc.edu
Front. Biosci. (Landmark Ed) 2019, 24(3), 431–442; https://doi.org/10.2741/4728
Published: 1 January 2019
Abstract

Cell polarity, the asymmetric distribution of proteins, organelles, and cytoskeleton, plays an important role in development, homeostasis, and disease. Understanding the mechanisms that govern cell polarity is critical for creating strategies to treat developmental defects, accelerate tissue regeneration, and hinder cancer progression. This review focuses on the role of cell polarity in a number of physiological processes, including asymmetric division, cell migration, immune response mediated by T lymphocytes, and cancer progression and metastasis, and highlights microfabrication techniques to systematically parse the role of microenvironmental cues in the regulation of cell polarity.

Keywords
Cell polarity
Cell fate
Cell asymmetry
Microfabrication
Review
2. INTRODUCTION

Cell polarization, defined as the asymmetric distribution of proteins, organelles, and cytoplasm, occurs in many forms (1). The most commonly known is the apical-basal polarity of epithelial cells. However there also exists front-to-back polarity of migrating cells and planar polarity, which organizes and polarizes the cells found in one plane of the tissue (2, 3). The mechanisms by which cells polarize have been studied in a wide range of organisms and appear to be evolutionarily conserved (4). However, there are various pathways for each type of polarity that requires the interaction of multiple signaling molecules (5, 6).

Polarization of cells has been demonstrated as a critical event in evolutionary biology. For single-cell organisms, such as budding yeast, polarization is the mechanism by which reproduction occurs (1). For more complex organisms, such as Caenorhabditis elegans (C. elegans) and Drosophila melanogaster (D. melanogaster), polarization results in the development and organization of different body parts, including the nervous system and wing organization (6, 7). Without polarization, complex organisms with a multitude of cell types would not exist, migration of cells would be impossible, and cells would not be able to properly perform their functions (8).

In this review, we examine the different ways cell polarization is involved in development, homeostasis, and disease. Table 1 summarizes provides a synopsis of published work on the role of cell polarity on cell function. We proceed to discuss how microfabrication techniques have enabled systematic studies of cell polarization, and we discuss the future efforts needed to improve these techniques.

Table 1.The impact of polarity on cell functions
Function Mechanism References
Asymmetric division Uneven distribution of key proteins known as fate determinants (including Numb, Brat, PAR, aPKC) and organelles during mitosis lead to asymmetric division 16 and 17
Development and differentiation Uneven distribution of key polarity proteins results in asymmetric division and differentiation of progenitor cells. This phenomenon along with the organism’s body axes in planar polarity are required for functional formation of wings, eyes, ears and other organs 6, 12, 16, and 27
Migration Polarity leads to upregulation and redistribution of proteins including Cdc42, Rac and PAR to the leading/front edge of the cell resulting in directional migration of cells 11, 31, and 32
Cancer Polarity contributes to the initiation of disease by increased asymmetric divisions and progression of disease through increased migration and metastasis by the upregulation of Cdc42 39, 42, 47
Immune Response Polarization of proteins and fate determinants during early encounters with antigen regulate T lymphocyte differentiation to effector or central memory phenotype 53, 54, and 55
3. POLARIZATION AND CELL FUNCTION

The morphology of cells is optimized to fulfill its function such as the propagation of signals through a neuron’s axon, or the squamous shape of epithelial cells that allow for selective solute transport (Figure 1) (1). The distinct shapes of cells seen in Figure 1 allow different cell types to perform their function of migrating or initiating immune responses. Cells that create compartments (e.g., epithelia) must be polarized to maintain contents in their corresponding partitions (9, 10). Epithelial cells have apical-basal polarity that allow specialized trafficking of solutes and planar polarity for organogenesis (6). The apical-basal polarity is a result of cell-cell and cell-extracellular matrix (ECM) interactions. Tight junctions between cells prevent proteins and ions from flowing freely between the apical and basal sides, effectively creating a barrier to prevent unwanted material from entering the body (Figure 1) (11). The development and maintenance of cell polarity is a result of multiple signals from polarity proteins, epithelial cadherin (E-cadherin) and focal adhesion contact with the ECM. These signals organize the cytoskeleton and aid in organelle localization. Loss of these signals results in differentiation from epithelial to mesenchymal cell types and front-to-back polarization (11).

Figure 1

Cell polarity plays a critical role in cell function. A prime example is the epithelial cells utilizing apical-basal polarity to provide a barrier function against pathogens. Another example is cell migration which requires front-to-back polarity to allow cells to adhere to and detach from the ECM. Polarity is also required for neurons to perform their task of propagating action potentials and sending messages from the central nervous system to distant body parts.

Planar cell polarization is more complex since it is not a direct result of cell-cell contact, but rather the positioning of the cell with respect to the organism’s body axes (6). This type of polarity is responsible for the organization of feathers on a bird or the orientation of a fly’s wing. Disruption of this type of polarity can result in improper development of the eye or the inner ear, resulting in blindness or deafness,(6) demonstrating how polarity plays a large role in cell function and the lack of appropriate polarization can have dire consequences to the organism.

Neurons must also be polarized to serve their function of propagating signals to distant parts of the body (Figure 1) (1). Neuronal development in vitro begins with the spreading of filopodia that grow into small neurites. One of these neurites is selected to become the axon and begins to grow more quickly than the others. Finally, the remaining neurites become dendrites and polarize (12). The process is slightly different in vivo but all neurons require polarization to function. The polarization is a result of signaling from various secreted factors and the formation of complexes, such as Par6-Par3-aPKC (important in asymmetric division and development of D. melanogaster) (12). Other important factors for neuronal polarity include cell division control homolog 42 (Cdc42), the Ras homolog gene family, member A (RhoA), and Ras-related C3 botulinum toxin substrate 1 (Rac1) (13, 14). These factors highlight the importance of the cytoskeleton in polarization of cells.

4. POLARIZATION IN ASYMMETRIC DIVISION AND DEVELOPMENT

The phenomenon of asymmetric cell division was first observed and recorded by Edwin Conklin in 1905 in the developing embryo of ascidians (15). Other organisms have since been studied, in particular D. melanogaster and C. elegans, and have elucidated two mechanisms of asymmetric cell division in development (16). In the intrinsic mechanism, polarization of regulators within the cell causes an uneven distribution of proteins during mitosis, resulting in daughter cells with different internal signals that lead to differing fates (Figure 2). In D. melanogaster, the intrinsic mechanism is used in the development of the nervous system. Here, asymmetric divisions of neuroblasts give rise to one neuroblast and one ganglion mother cell (GMC), which then divides into differentiated neurons. The fate of each cell is controlled by the polarized distribution of the protein Numb and the translational inhibitor Brat (16). These fate determinants polarize the cell by localizing at the basal membrane during mitosis and can only be found in the basal cell after division. The localization of these fate determinants to the basal membrane is thought to occur because of the accumulation of PAR (partition deficient) proteins and atypical protein kinase C (aPKC) at the apical side (17). As a result of this protein polarization, the basal cell becomes a GMC while the apical cell remains a neuroblast.

Figure 2

Cell divisions are controlled by internal and external signals. Symmetric divisions occur when there is an equal distribution of proteins, organelles, and cytoskeleton in the mother cell resulting in two daughter cells of the same fate. Asymmetric divisions through the intrinsic mechanism have an unequal distribution of proteins and fate determinants often resulting in daughter cells with different fates. Through the extrinsic mechanism, the cell divides symmetrically but daughter cells receive different signals from the microenvironment resulting in diverse cell fates.

The second mechanism of asymmetric division is known as the extrinsic mechanism. Here, cells rely on cues from the microenvironment, and asymmetric division occurs when the cell divides in a perpendicular fashion, resulting in one daughter cell that is proximal to the niche and the other that is distal (Figure 2) (17). This mechanism is more prominent in adult stem cells and best studied in D. melanogaster ovaries and testes, where direct attachment to the niche is required to maintain stemness (17-19). If a germline stem cell divides perpendicular to the niche, one of the daughter cells loses contact, stops receiving signals from the niche cells and begins to differentiate (19). The importance of polarity in asymmetric division has been confirmed in the development of C. elegans. The oocyte is not polarized before fertilization, however, the fertilization of the egg by the sperm causes a change in the cytoskeletal integrity affecting the cell contractility and polarization of the anterior and posterior PAR proteins (20-22). After the C. elegans egg is fertilized and polarized, the first division is asymmetric and results in a larger anterior body and a smaller posterior cell (23). The development of C. elegans is a continued series of asymmetric and symmetric divisions, governed by anterior-posterior polarity, resulting in the generation of the three germinal layers (ectoderm, mesoderm, and endoderm) (24, 25).

Asymmetric cell division is also critical in mammalian development but is not as well understood or studied because of the long cell cycles in mammals. Studies of the developing brain of mice show the complex development with changes from symmetric division to asymmetric division throughout the developmental process (16, 26). The symmetric divisions serve to increase the number of progenitor cells, while the asymmetric divisions generate one differentiated nerve cell and a radial glia cell (progenitor cell) (27). Neural development occurs in various stages that involve symmetric and asymmetric divisions and migration of the progenitor cells to the basal region of the neuroepithelium for terminal differentiation (17). The molecules that control asymmetric division in D. melanogaster are conserved in mammals, however, their roles as fate determinants have not been fully established—with some studies indicating that not all conserved determinants play the same role in asymmetric division in mammals (17). One determinant, Numb, has been shown to be critical in asymmetric division and subsequent fate specification in both invertebrates and vertebrates (27). Differential localization of Numb into only one of the daughter cells causes that cell to differentiate into a neuron, while the other daughter cell remains a progenitor cell. Recent findings by Jossin, et al. show how loss of the polarity protein Lethal giant larvae (Lgl) alone can result in catastrophic brain development leading to cortical heterotropia and drug resistant epilepsy (28). While this highlights the importance of polarity in brain development, further studies are still required to establish the mechanisms and the polarization of fate determinants that leads to asymmetric division in neurogenesis and mammalian development.

The importance of asymmetric division in development is clear. Organisms use symmetric divisions to clone cells and asymmetric divisions to give rise to new cells with different roles. Asymmetric division allows for the development of new cell types while maintaining a pool of progenitor cells. This physiologic process continues throughout the life of the organism and is involved in wound healing and tissue regeneration, adult stem cell differentiation, cancer, and immune responses (29, 30). All of these processes, however, would not be possible without the polarization of proteins, such as fate determinants, to induce these asymmetric cell divisions and create cellular diversity.

5. POLARIZATION AND MIGRATION

Migration of cells can occur in development, but also as a result of injury and disease progression. Microenvironmental cues cause the cell to organize its actin cytoskeleton and begin migration toward the signal. Some specialized cells, such as sperm, are always polarized and have cilia or flagella to help them migrate, while other cells polarize by growing lamellipodia or filopodia in response to stimuli (31). The stimuli cause activation of Rho family proteins, which influence the growth and attachment of actin chains (31). Cell migration can occur as a single cell or a sheet of cells, which is referred to as collective cell migration. Although the same mechanisms are required for both migration methods, collective cell migration requires synchronization among all the cells to move without disrupting cell-cell contacts (32).

Regardless of migration type, all migratory cells express mesenchymal genes and have front-rear polarity (11, 32). The front leading edge of migrating cells has proteins such as Cdc42, PAR, and activated Rac, and in some cells a microtubule organizing center. These proteins work by controlling microtubule growth and therefore where lamellipodia form. This control in lamellipodia localization results in organized migration. Since the rear of the cell lacks these proteins, protrusion extensions are prevented resulting in directional migration (31).

6. POLARIZATION AND CANCER

Cancer is caused by the abnormal over-proliferation of cells. This unchecked growth can be caused by a large variety of mutations (33-35). A contributing factor towards this dysregulation is the mutation of fate determinants or polarity proteins leading to decreased asymmetric division. These mutations prevent asymmetric division from occurring but do not stop the cell from cycling and dividing, thereby resulting in an increased number of symmetric divisions and an increase in progenitor cells (36). This increase in progenitor cells increases the amount of differentiated cells resulting in a neoplasm. This explanation agrees with the hypothesis of cancer stem cells, which are cells capable of producing all the cell types in a tumor and have stem cell markers such as those found in early progenitor cells that have not differentiated (16, 37). Although the mechanisms of asymmetric division in mammals are poorly understood, studies have focused on the loss of Numb regulation as a possible explanation for cancer propagation as a result of an imbalance of asymmetric division (38). Understanding the mechanisms by which healthy cells lose their ability to divide asymmetrically can help us determine new targets for cancer treatment, including possibly chemo- and radiotherapy-resistant cancer cells.

While loss of polarization and asymmetric division is thought to play a large role in cancer, the polarization of cancer cells can help advance the disease by causing metastasis (39-41). Metastasis, the complex process of establishing a new tumor at a distant site, requires that the cells first lose their epithelial polarity from cell-cell contact and regain front-to-back polarity to migrate into the circulation and extravasate at distant sites (39). The process of epithelial to mesenchymal transition, which is also important during development, is believed to be the mechanism by which metastasis begins (39, 42, 43). As one of the key regulators of cell polarity, Cdc42 has been shown to be upregulated in cancer cells and integral in the metastatic process (31, 44, 45). Reymond et al. used siRNA to show that silencing Cdc42, by even just a transient depletion, prevents metastases to the lung by decreasing beta1 integrin levels and intercalation of cancer cells into the endothelial layers (44). These results showed that Cdc42 was required for transendothelial migration and that a reduction in Cdc42 levels was enough to reduce cancer cell migration and metastasis. Another group found similar results including a target (miR137) that can reduce Cdc42 levels and reduce colorectal cancer cell invasion (46). Furthermore, Kamai et al. showed that higher expression of Cdc42 correlated with more advanced disease, furthering evidence that Cdc42 is crucial in cancer cell invasion and metastasis (47). Together, these studies show how levels of Cdc42, a known polarity regulator, play an important role in cancer progression and suggest mechanisms by which Cdc42 levels can be controlled.

7. POLARIZATION AND THE IMMUNE SYSTEM

The effects of asymmetric cell division in the immune system have been more difficult to study because of the motile nature of these cells. Studies are further complicated by a slow differentiation rate and the subtle morphological changes that occur during differentiation. The relatively few hematopoietic cells present in the body also make it difficult to find and track individual cells undergoing asymmetric division in vivo (23, 48). Because of these hinderances, it is still unclear whether hematopoietic stem cells (HSCs) use asymmetric divisions as the mechanism to differentiate into different lineages. Studies suggest that Numb and alpha-Adaptin (an important protein in D. melanogaster asymmetric division) may play a role in the asymmetric division of HSCs (49, 50). Other proteins have been found to asymmetrically localize in HSCs, resulting in one daughter cell that is more primitive than the other, confirming that intrinsic asymmetric division occurs (51).

While studies have shown that asymmetric division does not appear to play a large role in B cell development and differentiation, it does appear to influence T cells (23, 52). The polarization and asymmetric division of polarity proteins and fate determinants is thought to occur after activation of the T cell through the T-cell receptor and antigen-presenting cell (53). The activation of the T cell results in divisions that create two types of T cells: the memory T cell and the effector T cell. Memory T cells can further asymmetrically divide to give rise to the more differentiated effector T cell phenotype and maintain the memory T cell pool, indicating a stem cell-like behavior (54).

Mechanistic studies into asymmetric division of T cells show that different determinants play a role during the primary and secondary immune response. In the primary response, CD3 and Interferon-gamma receptor (INF-gammaR) asymmetrically locate in memory cells but show little asymmetry in effector T cells (54). Further exposure to the antigen can cause the central memory T cells to mount a secondary immune response. Here, they again divide asymmetrically to produce daughter cells that are effector T cells and central memory cells. CD25 and T-bet (T cell transcription factor regulating T helper cell lineage commitment) polarize to the effector T cell, leaving low levels of both on the other daughter cell, which remains a memory T cell (54). Interestingly, the polarization of protein kinase C zeta type (PKC-zeta) differs between the primary response and the secondary response, suggesting that PKC-zeta may play a role in establishing central memory (54).

Previous studies have discovered important proteins that are polarized in T cells and regulate morphology, migration, and cell fate (55). For example, T cells exposed to antigen via dendritic cells polarized aPKC and Par3 proteins distal to the dendritic cell while Scribble and Discs large (Dlg), two important polarity proteins that form the Scribble complex, localized proximally (55). This proved that T cells use evolutionarily conserved mechanisms found in many organisms and cell types to asymmetrically divide. This study further showed that this polarity was important in memory T cell differentiation but not in effector T cell differentiation (55). Another group found that Scribble plays a major role in polarity and downregulation leading to decreased polarity and ability of T cells to migrate and present antigen (56). Thus, polarity in T cells is important for differentiation and gives the T cell the ability to perform the function of antigen presentation to mount an immune response.

8. MICROFABRICATION TECHNIQUES TO STUDY CELL POLARITY

Microfabrication techniques have been used to understand the mechanisms responsible for asymmetric cell divisions and cell polarization and their effects on cell fate and behavior, including the use of hydrogels, microfluidic devices, and cell encapsulating scaffolds (57, 58). By utilizing these systems, many biological parameters that cannot be manipulated in ordinary cell culture can now be controlled, allowing for a systematic study of individual cell properties of interest. These systems can also be utilized to better mimic biological environments in vitro, providing valuable insight into cellular behavior in vivo.

One of the simplest ways to create these environments is by using microcontact printing to produce adhesive regions of varying geometries (59). This technique has been used to study various biological phenomena such as the asymmetric division of mesenchymal stem cells (MSCs) and migration of fibroblasts and cancer cells (57, 60). Asymmetric patterns, created using microcontact printing, were able to polarize the cell by asymmetric organization of the actin and microtubule cytoskeleton and resulted in biased segregation of DNA (57). This biased segregation was found primarily in stem cells and believed to play a role in stem cell differentiation. Work by Thery et al. demonstrated that anisotropy in the ECM created via micropatterns imposed polarity in epithelial cells by examining the organization of the actin cytoskeleton as well as the localization of the nucleus and the Golgi apparatus (61). That study not only showed the importance of ECM geometry but provided a tool for controlling cell polarity to determine its effects on cell behavior.

Micropatterns have also been used to study the effects of cell polarization on cell migration. Jiang et al. was able to demonstrate that the control of cell shape asymmetry via asymmetric micropatterns could bias the direction of cell migration (62). In this study, cells were confined to various symmetric and asymmetric micropatterns, then released to examine the direction of migration. The results demonstrated that cell polarity biases the direction of migration even after the cell was no longer confined to the original geometry. Similarly, Mahmud et al. created different symmetric and asymmetric “ratchet” micropatterns and showed that they caused directional migration while the cells remained in contact with the surface features (60). Various cell types (e.g., normal and cancer cells) were used and the short-term and long-term directional biases were studied. The micropatterns polarized the Arp2/3 complex and the actin cytoskeleton leading to directional movement of different cell types and sorting cells into individual reservoirs (60).

Further studies into the mechanisms of biased cell migration using micropatterns have shown mixed results. Kushiro et al. found that lamellipodial extensions, controlled by Rac1, play a major role in migration directional bias (63). However, Kumar et al. found that directional bias was not significantly altered by changes in Rac1, RhoA, or Cdc42 expression (64). While these studies seem to contradict each other, there were various differences between the two studies that provide further clues into biased cell migration mechanisms. In the Kushiro study MCF-10A (human mammary epithelial) cells were used while Kumar used NIH3T3 fibroblasts. Furthermore, the manipulation to the proteins of interest was also different, Kushiro suppressed Rac1 expression while Kumar’s study constitutively expressed Rac1, RhoA and Cdc42. This suggests that Rac1 is important in selecting migration direction, but an overexpression does not alter this directional bias. Although not fully explained, these studies begin to unravel the complexities of regulating cell migration of polarized cells.

Several groups have employed micropatterning to study the role of polarity in cell fate specification. A study by Peng, et al. found that cell anisotropy, induced as a result of the increased aspect ratio of the underlying micropattern, decreased adipogenic differentiation in MSCs and found that the optimal aspect ratio for osteogenesis was 2 (65). While the mechanism for this phenomenon was not fully explained, it was suggested that anisotropy alters forces from the cytoskeleton and results in modified gene expression and stem cell differentiation. A study by Harris et al. showed that MSCs on rectangles differentiated to osteoblasts in both soft and stiff matrices, while cells on squares only favored osteogenesis on the stiff matrix (66). While the aspect ratio of the rectangle was not reported, this study corroborates the results of Peng’s work that shape and polarization caused by changes in geometric aspect ratio play a role in stem cell fate (66). Recently, we created symmetric and asymmetric micropatterned hydrogels to study the role of polarity in MSC differentiation. We found that cells seeded on asymmetric micropatterns had a higher amount of osteogenesis compared to cells on symmetric micropatterns and therefore concluded that polarity signals increase osteogenic differentiation in human MSCs (67).

Micropatterning of macrophages onto elongated patterns showed that anisotropy caused M2 polarization without the presence of cytokines (68). Mechanistic studies found that the cytoskeleton played a critical role in the M2 polarization. While only a few studies of these phenomena are published, the results show the importance of cell polarity on the cytoskeleton organization and how this organization affects cell fate. Follow up studies are needed to determine the mechanisms behind polarity and cell differentiation so better tissue engineering strategies can be developed.

Asymmetric divisions depend on the orientation of the division axis, which is controlled by cortical cues including cell polarity and cell-ECM contact. Théry was able to show that asymmetric micropatterns could affect these cortical cues and change the orientation of the division axis in HeLa cells. This study shows that not all asymmetric micropatterns result in a spindle orientation that would result in asymmetric division. Instead the orientation is controlled by the torque generated by the retraction fibers and the cortical cues (58). This again demonstrates the importance of the cytoskeleton and how its organization can influence cell polarity and asymmetric division. Further investigation into these micropatterns that bias asymmetric division can provide insight into their effects on cell fate and other cellular behaviors.

Several other microfabrication techniques have also been employed to induce cell polarity, including carbon nanotubes, coated substrates and microfluidic devices. By aligning carbon nanotubes, Cheng et al. was able to control the distribution of focal adhesions, cell alignment, and polarity in both human umbilical vascular endothelial cells and human embryonic stem cells (69). Scaffolds with tailored substrates are another way to create three dimensional (3D) structures which guide cell phenotype. These scaffolds can be made of various materials, such as polymers, ceramics or metals and scaffold design should be customized for the biological environment being mimicked and the cell type used (70-72). As an example, Granziano et al. used scaffolds with tailored surface geometry to polarize dental pulp stem cells to enhance differentiation as well as proliferation (73). In this study, scaffolds with microconcavities that mimicked the architecture of bone marrow resulted in greater osteogenesis. In another recent study, Wang et al. successfully created collagen scaffolds that resembled the small intestine in guiding epithelial cells apical-basal polarity and directional migration (74). Cells in the crypt remained undifferentiated and migrated toward the villi leading to the creation of tissue architecture of small intestine. This approach has also been utilized using hydrogels of polyethylene glycol (PEG) to elucidate dynamic cell-material interaction and matrix remodeling in cell migration in the context of regenerative medicine (75).

Microfluidic devices have also been proven to be powerful tools for modeling and studying cell polarity and chemotaxis in 3D (76, 77). Because these devices are usually clear, they allow for real time measurements and visualization of cell migration that other 3D culture conditions cannot. These devices can be used to decipher the mechanisms involved in cell migration and have most often been used to characterize cell migration in healthy and cancer cells (77-79). A recent study created a microfluidic device using selective curing that incorporated electrospun fibers (80). Breast cancer cells were able to migrate through the membrane toward the chemoattractant. This new platform can control various aspects of the tumor microenvironment to determine how they affect cell behavior and polarity. By using this systematic platform, methodical testing can be performed to understand how the cell-ECM interactions lead to specific cellular behaviors, such as metastasis in cancer cells. Another group created a microfluidic device without a chemotactic gradient to monitor how cancer cells move in confined spaces in response to chemotherapeutic drugs (81). The authors found that migration still occurred when the cells were exposed to drug concentrations above those required to stop proliferation, suggesting that these cells can survive treatment, migrate to distant sites, and metastasize.

9. CONCLUSIONS

The importance of cell polarization is evident by the various functions it has in biology and by the detrimental diseases caused by its dysregulation. Our current understanding of the mechanisms used to induce cell polarity have been mainly limited to using C. elegans and D. melanogaster mutants. This knowledge is the basis for examining mammalian development and many key molecules have been found to be conserved between organisms. However, the complexities of mammals make mechanistic studies in vitro quite difficult. Microfabrication techniques provide a powerful tool to systematically study polarization in vitro to parse the role of physiological cues that govern polarization and contribute to the progression of disease states.

Further, this insight will provide a rational basis for designing stem cell culture systems and facilitate their use in regenerative medicine.

10. ACKNOWLEDGEMENTS

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number AR063338.

References
[1]
W.J.Nelson Adaptation of core mechanisms to generate cell polarity. Nature, 4226933 76674 2003doi:10.1038/nature01602https://doi.org/10.1038/nature01602
[2]
Y.GongC.Mo andS.E.Fraser Planar cell polarity signalling controls cell division orientation during zebrafish gastrulation. Nature, 4306892004doi:10.1038/nature02796https://doi.org/10.1038/nature02796
[3]
M.Vicente-ManzanaresD.J.Webb andA.R.Horwitz Cell migration at a glance. J Cell Sci, 11821 49174919 2005doi:10.1242/jcs.02662https://doi.org/10.1242/jcs.02662
[5]
S.Etienne-MannevilleA.Hall Cell polarity: Par6, aPKC and cytoskeletal crosstalk. Curr Opin Cell Biol, 151 6772 2003doi:https://doi.org/10.1016/S0955-0674(02)00005-4https://doi.org/10.1016/S0955-0674(02)00005-4
[6]
M.Mlodzik Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet, 1811 56471 2002https://doi.org/10.1016/S0168-9525(02)02770-1
[7]
J.A.Knoblich Mechanisms of Asymmetric Stem Cell Division. Cell, 1324 583597 2008doi:https://doi.org/10.1016/j.cell.2008.02.007
[8]
T.Lechler andE.Fuchs Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature, 4377056 275280 2005doi:10.1038/nature03922https://doi.org/10.1038/nature03922
[9]
D.W.Powell: Barrier function of epithelia. Am J Physiol Gastrointest Liver Physiol, 2414 G275G288 1981doi:10.1152/ajpgi.1981.241.4.G275https://doi.org/10.1152/ajpgi.1981.241.4.G275
[10]
F.Pilot andT.Lecuit: Compartmentalized morphogenesis in epithelia: from cell to tissue shape. Dev Dyn, 2323 68594 2005doi:10.1002/dvdy.20334https://doi.org/10.1002/dvdy.20334
[11]
W.J.Nelson: Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol, 11 a000513 2009doi:10.1101/cshperspect.a000513https://doi.org/10.1101/cshperspect.a000513
[12]
T.Takano,C.Xu,Y.Funahashi,T.Namba andK.Kaibuchi Neuronal polarization. Development, 14212 20882093 2015doi:10.1242/dev.114454https://doi.org/10.1242/dev.114454
[13]
H.Witte andF.Bradke: The role of the cytoskeleton during neuronal polarization. Curr Opin Neurobiol, 185 47987 2008doi:10.1016/j.conb.2008.09.019https://doi.org/10.1016/j.conb.2008.09.019
[14]
E.E.Govek,Z.Wu,D.Acehan,H.Molina,K.Rivera,X.Zhu,Y.FangM.Tessier-LavigneM.E.Hatten Cdc42 Regulates Neuronal Polarity during Cerebellar Axon Formation and Glial-Guided Migration. iScience, 1 3548 2018doi.org/10.1016/j.isci.2018.01.004https://doi.org/10.1016/j.isci.2018.01.004
[15]
E.G.Conklin The Organization and Cell-lineage of the Ascidian Egg. Philadephia, PA 1905PMid:17770960
[16]
J.A.Knoblich Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol, 1112 84960 2010doi:10.1038/nrm3010https://doi.org/10.1038/nrm3010
[17]
J.A.Knoblich Mechanisms of asymmetric stem cell division. Cell, 1324 58397 2008doi:10.1016/j.cell.2008.02.007https://doi.org/10.1016/j.cell.2008.02.007
[18]
S.J.Morrison andA.C.Spradling Stem Cells and Niches: Mechanisms That Promote Stem Cell Maintenance throughout Life. Cell, 1324 598611 2008doi:https://doi.org/10.1016/j.cell.2008.01.038
[19]
M.T.Fuller andA.C.Spradling: Male and Female Drosophila Germline Stem Cells: Two Versions of Immortality. Science, 3165823 402404 2007doi:10.1126/science.1140861https://doi.org/10.1126/science.1140861
[20]
S.Q.Schneider andB.Bowerman Cell polarity and the cytoskeleton in the Caenorhabditis elegans zygote. Annu Rev Genet, 37 22149 2003doi:10.1146/annurev.genet.37.110801.142443https://doi.org/10.1146/annurev.genet.37.110801.142443
[21]
R. A.NeumüllerJ.A.Knoblich Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev, 2323 26752699 2009doi:10.1101/gad.1850809https://doi.org/10.1101/gad.1850809
[22]
S.Guo andK.J.Kemphues: par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 814 611620 1995doi:https://doi.org/10.1016/0092-8674(95)90082-9https://doi.org/10.1016/0092-8674(95)90082-9
[23]
K.Pham,F.Sacirbegovic andS.M.Russell: Polarized cells, polarized views: asymmetric cell division in hematopoietic cells. Front Immunol, 5262014doi:10.3389/fimmu.2014.00026https://doi.org/10.3389/fimmu.2014.00026
[24]
C.Q.Doe andB.Bowerman: Asymmetric cell division: fly neuroblast meets worm zygote. Curr Opin Cell Biol, 131 6875 2001doi:https://doi.org/10.1016/S0955-0674(00)00176-9https://doi.org/10.1016/S0955-0674(00)00176-9
[25]
C.E.Rocheleau,W.D.Downs,R.Lin,C.Wittmann,Y.Bei, Y.-H.Cha,M.Ali,J.R.Priess andC.C.Mello: Wnt Signaling and an APC-Related Gene Specify Endoderm in Early C. elegans Embryos. Cell, 904 707716 1997doi:https://doi.org/10.1016/S0092-8674(00)80531-0https://doi.org/10.1016/S0092-8674(00)80531-0
[26]
M.GötzW.B.Huttner The cell biology of neurogenesis. Nat Rev Mol Cell Biol, 67772005doi:10.1038/nrm1739https://doi.org/10.1038/nrm1739
[27]
Q.Shen,W.Zhong,Y.N.Jan andS.Temple Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts. Development, 12920 48434853 2002https://www.nature.com/articles/ncomms14684#supplementary-information">PMid:12361975
[28]
Y.Jossin,M.Lee,O.Klezovitch,E.Kon,A.Cossard, W.-H.LienT.E.Fernandez,J.A.Cooper andV.Vasioukhin Llgl1 Connects Cell Polarity with Cell-Cell Adhesion in Embryonic Neural Stem Cells. Dev Cell, 415 481495.e5 2017doi.org/10.1016/j.devcel.2017.05.002https://doi.org/10.1016/j.devcel.2017.05.002
[29]
G.Mascré,S.Dekoninck,B.Drogat,K.K.Youssef, S.BrohéeP.A.Sotiropoulou,B.D.Simons andC.Blanpain: Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature, 4892572012doi:10.1038/nature11393https://doi.org/10.1038/nature11393
[30]
M.Aragona,S.Dekoninck,S.Rulands,S.Lenglez, G.Mascré,B.D.Simons andC.Blanpain Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat Commun, 8146842017doi:10.1038/ncomms14684https://doi.org/10.1038/ncomms14684
[31]
A.J.Ridley,M.A.Schwartz,K.Burridge,R.A.Firtel,M.H.Ginsberg,G.Borisy,J.T.Parsons andA.R.Horwitz Cell migration: integrating signals from front to back. Science, 3025651 17049 2003doi:10.1126/science.1092053https://doi.org/10.1126/science.1092053
[32]
P.Friedl andD.Gilmour Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol, 107 44557 2009doi:10.1038/nrm2720https://doi.org/10.1038/nrm2720
[33]
J.M.Adams andS.Cory The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene, 269 13241337 2007doi:10.1038/sj.onc.1210220https://doi.org/10.1038/sj.onc.1210220
[34]
P. A. J.MullerK.H.Vousden p53 mutations in cancer. Nat Cell Biol, 1522013doi:10.1038/ncb2641https://doi.org/10.1038/ncb2641
[35]
P.J.Stephens,C.D.Greenman,B.Fu,F.Yang,G.R.Bignell,L.J.Mudie,E.D.Pleasance,K.W.Lau,D.Beare,L.A.Stebbings,S.McLaren, M.-L.LinD.J.McBride,I.Varela, S.Nik-ZainalC.Leroy,M.Jia,A.Menzies,A.P.Butler,J.W.Teague,M.A.Quail,J.Burton,H.Swerdlow,N.P.Carter,L.A.Morsberger, C.Iacobuzio-DonahueG.A.Follows,A.R.Green,A.M.Flanagan,M.R.Stratton,P.A.Futreal andP.J.Campbell: Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development. Cell, 1441 2740 2011doi:https://doi.org/10.1016/j.cell.2010.11.055
[36]
S.J.Morrison andJ.Kimble: Asymmetric and symmetric stem-cell divisions in development and cancer. Nature, 4417097 106874 2006doi:10.1038/nature04956https://doi.org/10.1038/nature04956
[37]
S.Mukherjee,J.Kong andD.J.Brat: Cancer stem cell division: when the rules of asymmetry are broken. Stem Cells Dev, 244 40516 2015doi:10.1089/scd.2014.0442https://doi.org/10.1089/scd.2014.0442
[38]
J.Bajaj,B.Zimdahl andT.Reya: Fearful symmetry: subversion of asymmetric division in cancer development and progression. Cancer Res, 755 7927 2015doi:10.1158/0008-5472.can-14-2750https://doi.org/10.1158/0008-5472.CAN-14-2750
[39]
J.Yang,S.A.Mani,J.L.Donaher,S.Ramaswamy,R.A.Itzykson,C.Come,P.Savagner,I.Gitelman,A.Richardson andR.A.Weinberg: Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis. Cell, 1177 927939 2004doi:https://doi.org/10.1016/j.cell.2004.06.006
[40]
J.Sakakibara,M.Sakakibara,N.Shiina,T.Fujimori,Y.Okubo,K.Fujisaki,T.Nagashima,T.Sangai,Y.Nakatani andM.Miyazaki: Expression of cell polarity protein scribble differently affects prognosis in primary tumor and lymph node metastasis of breast cancer patients. Breast Cancer, 243 393399 2017DOI 10.1007/s12282-016-0715-2https://doi.org/10.1007/s12282-016-0715-2
[41]
B.Liu,J.Xiong,G.Liu,J.Wu,L.Wen,Q.Zhang andC.Zhang: High expression of Rac1 is correlated with partial reversed cell polarity and poor prognosis in invasive ductal carcinoma of the breast. Tumor Biol, 39710104283177109082017doi: 10.1177/1010428317710908https://doi.org/10.1177/1010428317710908
[42]
A.Voulgari andA.Pintzas: Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta, 17962 7590 2009doi:10.1016/j.bbcan.2009.03.002https://doi.org/10.1016/j.bbcan.2009.03.002
[43]
Y.Kang and J.Massagué Epithelial-Mesenchymal Transitions: Twist in Development and Metastasis. Cell, 1183 277279 2004doi:https://doi.org/10.1016/j.cell.2004.07.011
[44]
N.Reymond,J.H.Im,R.Garg,F.M.Vega, B.Borda d’AguaP.Riou,S.Cox,F.Valderrama,R.J.Muschel andA.J.Ridley: Cdc42 promotes transendothelial migration of cancer cells through β1 integrin. J Cell Biol, 1994 653668 2012doi:10.1083/jcb.201205169https://doi.org/10.1083/jcb.201205169
[45]
G.L.Razidlo,K.M.Burton andM.A.McNiven Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem, jbc. RA118.0032762018https://doi.org/10.1074/jbc.ra118.003276
[46]
M.Liu,N.Lang,M.Qiu,F.Xu,Q.Li,Q.Tang,J.Chen,X.Chen,S.Zhang,Z.Liu,J.Zhou,Y.Zhu,Y.Deng,Y.Zheng andF.Bi miR-137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells. Int J Cancer, 1286 12691279 2011doi:10.1002/ijc.25452https://doi.org/10.1002/ijc.25452
[47]
T.Kamai,T.Yamanishi,H.Shirataki,K.Takagi,H.Asami,Y.ItoK.-I.Yoshida Overexpression of RhoA, Rac1, and Cdc42 GTPases Is Associated with Progression in Testicular Cancer. Clin Cancer Res, 1014 47994805 2004doi:10.1158/1078-0432.ccr-0436-03https://doi.org/10.1158/1078-0432.CCR-0436-03
[48]
J.Arsenio,P.J.Metz andJ.T.Chang Asymmetric Cell Division in T Lymphocyte Fate Diversification. Trends Immunol, 3611 670683 2015doi:10.1016/j.it.2015.09.004https://doi.org/10.1016/j.it.2015.09.004
[49]
M.Wu,H.Y.Kwon,F.Rattis,J.Blum,C.Zhao,R.Ashkenazi, TrachetteL.Jackson,N.Gaiano,T.Oliver andT.Reya Imaging Hematopoietic Precursor Division in Real Time. Cell Stem Cell, 15 541554 2007doi:https://doi.org/10.1016/j.stem.2007.08.009
[50]
S.B.Ting,E.Deneault,K.Hope,S.Cellot,J.Chagraoui,N.Mayotte,J.F.Dorn,J.P.Laverdure,M.Harvey,E.D.Hawkins,S.M.Russell,P.S.Maddox,N.N.Iscove andG.Sauvageau Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2. Blood, 11911 251022 2012doi:10.1182/blood-2011-11-393272https://doi.org/10.1182/blood-2011-11-393272
[51]
J.Beckmann,S.Scheitza,P.Wernet,J.C.Fischer andB.Giebel Asymmetric cell division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins. Blood, 10912 54945501 2007doi:10.1182/blood-2006-11-055921https://doi.org/10.1182/blood-2006-11-055921
[52]
K.R.Duffy,C.J.Wellard,J.F.Markham, J. H. S.Zhou,R.Holmberg,E.D.Hawkins,J.Hasbold,M.R.Dowling andP.D.Hodgkin Activation-Induced B Cell Fates Are Selected by Intracellular Stochastic Competition. Science, 3356066 338341 2012doi:10.1126/science.1213230https://doi.org/10.1126/science.1213230
[53]
J.T.Chang,V.R.Palanivel,I.Kinjyo,F.Schambach,A.M.Intlekofer,A.Banerjee,S.A.Longworth,K.E.Vinup,P.Mrass,J.Oliaro,N.Killeen,J.S.Orange,S.M.Russell,W.Weninger andS.L.Reiner Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses. Science, 3155819 16871691 2007doi:10.1126/science.1139393https://doi.org/10.1126/science.1139393
[54]
M.L.Ciocca,B.E.Barnett,J.K.Burkhardt,J.T.Chang andS.L.Reiner Asymmetric memory T cell division in response to re-challenge. J Immunol, 1889 41454148 2012doi:10.4049/jimmunol.1200176https://doi.org/10.4049/jimmunol.1200176
[55]
J.Oliaro, V.Van HamF.Sacirbegovic,A.Pasam,Z.e.Bomzon,K.Pham,M.J.Ludford-Menting,N.J.Waterhouse,M.Bots,E.D.Hawkins,S.V.Watt,L.A.Cluse, C. J. P.ClarkeD.J.Izon,J.T.Chang,N.Thompson,M.Gu,R.W.Johnstone,M.J.Smyth,P.O.Humbert,S.L.Reiner andS.M.Russell Asymmetric Cell Division of T Cells upon Antigen Presentation Uses Multiple Conserved Mechanisms. J Immunol, 1851 367375 2010doi:10.4049/jimmunol.0903627https://doi.org/10.4049/jimmunol.0903627
[56]
M. J.Ludford-MentingJ.Oliaro,F.Sacirbegovic,E.T.Cheah,N.Pedersen,S.J.Thomas,A.Pasam,R.Iazzolino,L.E.Dow,N.J.Waterhouse,A.Murphy,S.Ellis,M.J.Smyth,M.H.Kershaw,P.K.Darcy,P.O.Humbert andS.M.Russell A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity, 226 73748 2005doi:10.1016/j.immuni.2005.04.009https://doi.org/10.1016/j.immuni.2005.04.009
[57]
D.Freida,S.Lecourt,A.Cras,V.Vanneaux,G.Letort,X.Gidrol,L.Guyon,J.Larghero andM.Thery Human Bone Marrow Mesenchymal Stem Cells Regulate Biased DNA Segregation in Response to Cell Adhesion Asymmetry. Cell Rep, 53 601610 2013doi:https://doi.org/10.1016/j.celrep.2013.09.019
[58]
M.Théry A.Jiménez-DalmaroniV.Racine,M.Bornens and F.Jülicher Experimental and theoretical study of mitotic spindle orientation. Nature, 4474932007doi:10.1038/nature05786https://doi.org/10.1038/nature05786
[59]
Y.Li andK.A.Kilian Bridging the Gap: From 2D Cell Culture to 3D Microengineered Extracellular Matrices. Adv Healthc Mater, 418 27802796 2015doi:10.1002/adhm.201500427https://doi.org/10.1002/adhm.201500427
[60]
G.Mahmud,C.J.Campbell, K. J. M.BishopY.A.Komarova,O.Chaga,S.Soh,S.Huda, K.Kandere-GrzybowskaB.A.Grzybowski Directing cell motions on micropatterned ratchets. Nat Phys, 56062009doi:10.1038/nphys1306https://doi.org/10.1038/nphys1306
[61]
M.ThéryV.Racine,M.Piel, A.PépinA.Dimitrov,Y.Chen, J.-B.SibaritaM.Bornens Anisotropy of cell adhesive microenvironment governs cell internal organization and orientation of polarity. Proc Natl Acad Sci U S A, 10352 1977119776 2006doi:10.1073/pnas.0609267103https://doi.org/10.1073/pnas.0609267103
[62]
X.Jiang,D.A.Bruzewicz,A.P.Wong,M.Piel andG.M.Whitesides Directing cell migration with asymmetric micropatterns. . Proc Natl Acad Sci U S A, 1024 975978 2005doi:10.1073/pnas.0408954102https://doi.org/10.1073/pnas.0408954102
[63]
K.Kushiro,S.Chang andA.R.Asthagiri Reprogramming directional cell motility by tuning micropattern features and cellular signals. Adv Mater, 2240 45169 2010doi:10.1002/adma.201001619https://doi.org/10.1002/adma.201001619
[64]
G.Kumar,C.C.Co and C.-C.Ho Steering Cell Migration Using Microarray Amplification of Natural Directional Persistence. Langmuir, 277 38033807 2011doi:10.1021/la2000206https://doi.org/10.1021/la2000206
[65]
R.Peng,X.Yao andJ.Ding Effect of cell anisotropy on differentiation of stem cells on micropatterned surfaces through the controlled single cell adhesion. Biomaterials, 3232 804857 2011doi:10.1016/j.biomaterials.2011.07.035https://doi.org/10.1016/j.biomaterials.2011.07.035
[66]
G.M.Harris,M.E.Piroli andE.Jabbarzadeh: Deconstructing the Effects of Matrix Elasticity and Geometry in Mesenchymal Stem Cell Lineage Commitment. Adv Funct Mater, 2416 23962403 2014doi:doi:10.1002/adfm.201303400https://doi.org/10.1002/adfm.201303400
[67]
M.E.Piroli andE.Jabbarzadeh: Matrix Stiffness Modulates Mesenchymal Stem Cell Sensitivity to Geometric Asymmetry Signals. Ann Biomed Eng 2018doi:10.1007/s10439-018-2008-8https://doi.org/10.1007/s10439-018-2008-8
[68]
F.Y.McWhorter,T.Wang,P.Nguyen,T.Chung andW.F.Liu Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci U S A, 11043 1725317258 2013doi:10.1073/pnas.1308887110https://doi.org/10.1073/pnas.1308887110
[69]
Q.Cheng,G.M.Harris, M.-O.BlaisK.Rutledge andE.Jabbarzadeh: Alignment of Carbon Nanotubes: An Approach to Modulate Cell Orientation and Asymmetry. Nano LIFE, 4114500022014doi:10.1142/S1793984414500020https://doi.org/10.1142/S1793984414500020
[70]
B.B.Rothrauff,B.B.Lauro,G.Yang,R.E.Debski,V.Musahl andR.S.Tuan Braided and Stacked Electrospun Nanofibrous Scaffolds for Tendon and Ligament Tissue Engineering. Tissue Eng Part A, 239, 378389 2017 doi:10.1089/ten.tea.2016.0319https://doi.org/10.1089/ten.tea.2016.0319
[71]
E.Shamirzaei Jeshvaghani L.Ghasemi-MobarakehR.Mansurnezhad,F.Ajalloueian,M.Kharaziha,M.Dinari, M.Sami Jokandan S.Chronakis Ioannis Fabrication, characterization, and biocompatibility assessment of a novel elastomeric nanofibrous scaffold: A potential scaffold for soft tissue engineering. J Biomed Mater Res B Appl Biomater, 00 2017doi:10.1002/jbm.b.34043https://doi.org/10.1002/jbm.b.34043
[72]
W.Nie,C.Peng,X.Zhou,L.Chen,W.Wang,Y.Zhang,P.X.Ma andC.He Three-dimensional porous scaffold by self-assembly of reduced graphene oxide and nano-hydroxyapatite composites for bone tissue engineering. Carbon, 116 325337 2017doi:https://doi.org/10.1016/j.carbon.2017.02.013
[73]
A.Graziano, R.d'AquinoM. G.Cusella-De AngelisF.De FrancescoA.Giordano,G.Laino,A.Piattelli,T.TrainiA.De RosaG.Papaccio Scaffold's surface geometry significantly affects human stem cell bone tissue engineering. J Cell Physiol, 2141 16672 2008doi:10.1002/jcp.21175https://doi.org/10.1002/jcp.21175
[74]
Y.Wang,D.B.Gunasekara,M.I.Reed,M.DiSalvo,S.J.Bultman,C.E.Sims,S.T.Magness andN.L.Allbritton A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium. Biomaterials, 128 4455 2017doi:https://doi.org/10.1016/j.biomaterials.2017.03.005
[75]
K.M.Schultz,K.A.Kyburz andK.S.Anseth Measuring dynamic cell-material interactions and remodeling during 3D human mesenchymal stem cell migration in hydrogels. Proc Natl Acad Sci U S A, 11229 E375764 2015doi:10.1073/pnas.1511304112https://doi.org/10.1073/pnas.1511304112
[76]
Y.Huang,B.Agrawal,D.Sun,J.S.Kuo andJ.C.Williams Microfluidics-based devices: New tools for studying cancer and cancer stem cell migration. Biomicrofluidics, 510134122011doi:10.1063/1.3555195https://doi.org/10.1063/1.3555195
[77]
A.Shamloo,N.Ma, M.-m.PooL.L.Sohn andS.C.Heilshorn Endothelial cell polarization and chemotaxis in a microfluidic device. Lab on a Chip, 88 12921299 2008doi:10.1039/B719788Hhttps://doi.org/10.1039/b719788h
[78]
S.-Y.ChengS.Heilman,M.Wasserman,S.Archer,M.L.Shuler andM.WuA hydrogel-based microfluidic device for the studies of directed cell migration. Lab on a Chip, 76 763769 2007https://doi.org/10.1039/b618463dPMid:17538719
[79]
S.Chung,R.Sudo,V.Vickerman,I.K.Zervantonakis andR.D.Kamm Microfluidic platforms for studies of angiogenesis, cell migration, and cell–cell interactions. Ann biomed eng, 383 11641177 2010https://doi.org/10.1007/s10439-010-9899-3PMid:20336839
[80]
H.Eslami AmirabadiS.SahebAli,J.P.Frimat,R.Luttge and J. M. J.den Toonder A novel method to understand tumor cell invasion: integrating extracellular matrix mimicking layers in microfluidic chips by “selective curing”. Biomed Microdevices, 194922017doi:10.1007/s10544-017-0234-8https://doi.org/10.1007/s10544-017-0234-8
[81]
D.Irimia andM.Toner Spontaneous migration of cancer cells under conditions of mechanical confinement(). Integr Biol (Camb), 10 506512 2009doi:10.1039/b908595ehttps://doi.org/10.1039/b908595e
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Share
Back to top