Nuclear mechanics during cell migration
Introduction
Cell migration is a complex physicochemical process which leads to translocation of the cell body across two-dimensional (2D) surfaces, through basement membranes, or through three-dimensional (3D) interstitial tissues [1]. During migration through 3D tissues, the stiffness and density of the surrounding extracellular matrix (ECM) present an additional physical challenge to the moving cell body. Two principal mechanisms are known by which migrating cells can overcome these constraints: firstly, proteolytic ECM degradation leading to gap widening and cell-generated trail formation and secondly, elastic and plastic deformations of the cell body to fit through the available space [2]. If a cell is unable to ‘squeeze’ through a particularly narrow region, it employs a third mechanism to maintain migration, that is, retraction of already established protrusions and repolarization to explore the adjacent environment for an alternative route, thereby bypassing the obstacle [3]. Consequently, translocation through 3D tissues is dependent on the deformability of both, the environment and the cell body.
The cell body consists of the plasma membrane surrounding the gel-like cytoplasm including small organelles (dimensions below the 1–2 μm range) and cytoskeletal filaments. These structures are morphologically adaptable enough to vigorously change and adjust to virtually any shape via a combination of firstly, fast (passive) mechanical deformation and secondly, slower cytoskeletal remodelling [4, 5•, 6]. Ultimately, cytoplasmic protrusions pass through gaps in the submicron range; this adaptability can be experimentally exploited to isolate protrusive cell regions including pseudopodia, filopodia and invadopodia using filters with pores sized of 1 μm and below [7, 8]. In contrast, the nucleus, the largest cellular organelle, is approximately 5–10 times stiffer than the surrounding cytoskeleton as it is mechanically stabilized by a constitutive network of structural proteins (see below); therefore it commonly resists large changes in shape [5•, 9, 10, 11, 12]. Consequently, for migration through small pores or 3D scaffolds, the nucleus can become the rate-limiting organelle [7, 13•, 14].
Nuclear shapes and sizes can vary widely between different cell types and even within cell lines; nonetheless, most cells imaged in situ or cultured in 3D substrates have ovoid or spherical shaped nuclei with diameters of 5–15 μm [15]. In 2D culture, cells often spread out significantly, resulting in more disk-shaped nuclei 10–20 μm in diameter and only a few micrometers in height [16]. In a few often highly mobile cell types, however, including myeloid and cancer cells, the nuclei are bean-shaped, lobulated or segmented (‘polymorphic’) (Table 1) and thus may develop greater morphological flexibility [14, 17] (Figure 1).
In vivo, the dimensions of structural pores available for migrating cells in basement membranes and interstitial connective tissue vary considerably, ranging from large gaps in the range of 30 μm and larger in loose connective tissue and lymph nodes [18, 19•] down to submicron pores in basement membranes [20]. For cells passing through pores which are smaller than the cell diameter, the extent of required cell deformation depends on whether the cell degrades the ECM proteolytically in regions of local compression, or not [21]. Surface-localized proteolytic cleavage of ECM fibers enlarges the available space and leads to the de novo formation of small tracks; the diameter of these tracks approximates the cross section of the cell and thereby reduces required cell deformation [13•, 22]. In both proteolytic and non-proteolytic migration through 3D tissues, the shapes of both cytoplasm und nucleus thus adopt their morphology and thereby minimize resistance towards tissue structures [3]. We here aim to integrate nuclear dynamics into the multistep model of cell migration through interstitial tissue and discuss the implications of nuclear mechanics for physiological and neoplastic cell migration and invasion.
Section snippets
Steps of cell migration
Dependent on whether proteases are utilized or not, cell migration in 3D environments consists of four or five respective steps which are executed in a concurrent and cyclic manner [1, 23] (Figure 2). First the cell polarizes by actin assembly into filaments which push the plasma membrane outward and form protrusions (step 1), followed by the interaction of cell protrusions with the extracellular tissue matrix (step 2). In proteolytic migration through 3D tissues, the proteolytic degradation
Molecular regulation of nuclear shape and rigidity
In interphase nuclei, the size, shape, and stiffness are determined by the nuclear envelope and the nuclear interior. The nuclear envelope consists of the inner and outer nuclear membrane, interconnected at the sites of nuclear pores, and the underlying nuclear lamina, a dense protein network mostly made of lamin proteins that are part of the intermediate filament family (Figure 3) [5•].
Implications for cell dynamics in immune cell function and cancer
Alterations of the expression of proteins involved in nuclear morphology and plasticity occur during physiological cell differentiation and activation, as well as in deregulated form in cancer.
Conclusions
Through its connection to the actin, tubulin and intermediate filament cytoskeleton, the nucleus is a major mechanosensory integrator. Because of its size and high rigidity, compared to all other cell compartments, it further imposes a major physical challenge for cells moving in 3D environments. Consequently, studies on nuclear mechanics and its implications for cell migration should preferentially focus on 3D in vitro and in vivo models. Whereas increased nuclear deformability offers an
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We gratefully acknowledge Uta Flucke for human soft tissue sarcoma and Willeke Blokx for melanoma samples, and Monika Zwerger for generating the lamin-modified MCF10A cells. This work was supported by the European Community (T3Net, European Training Network) to P.F., grant 917.10.364 by the Dutch Science Foundation (NWO) to K.W. and the National Institutes of Health grants HL082792 and NS059348 and the Cardiovascular Leadership Group Award to J.L.
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