Foot process

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Foot process
Glial Cell Types.png
This schematic illustrates the four different types of glial cells, all of which possess cellular processes: ependymal cells (light pink), astrocytes (green), microglia (red), and oligodendrocytes (light blue). Cell bodies of neurons are in yellow (Their axons are surrounded by myelin, produced by oligodendrocytes).
GFP and FP.jpg
An illustration of podocytes, which surround the glomerular capillaries with their cell bodies, primary processes and interdigitating foot processes (FPs).

Foot processes (may also be known as footplates or endfeet) are specialized protrusive cellular extensions that may exhibit a pyramidal or finger-like morphology.morphology. [1] [2] They are most evident in mural cells, that are associated with and ensheath walls of blood capillaries, such as pericytes, podocytes and astrocytes. [3]

Contents

Despite not being exclusive, [4] [5] the term foot process is commonly associated with podocytes, [6] and the term perivascular or pericapillary endfeet is commonly associated with astrocytes. [7] In podocytes, terminal foot processess are also named pedicels (from Latin pedīculus , "little foot"). [8]

Foot processes are also present in Müller cells (modified astrocytes of the retina), [8] pancreatic stellate cells, [9] dendritic cells, [10] oligodendrocytes, [11] and others. Microglia, which are notably smaller than macroglia, can also extend their foot processes to contact areas of capillaries that are devoid of astrocyte endfeet, and thereby contribute to the formation of the glia limitans. [12] The term foot process may also apply to the basal infoldings, which are indentations found in the basal surface of certain epithelial cells, such as the retinal pigment epithelium and the amniotic epithelium. [13] .

Cytology

Foot processes vs. lamellipodia and filopodia

The difference between foot processes, and lamellipodia, which are broad sheet-like protrusions, and filopodia, which are long slender pointed extensions, is that lamellipodia and filopodia are especially significant for cell movement and migration, and they are "macro" membrane protrusions. In contrast, many foot processes usually interact with basement membranes and other cells, and are usually present at the "micro" scale. [1]

Filopodia and lamellipodia in two fluorescently-labeled growth cones. GrowthCones.jpg
Filopodia and lamellipodia in two fluorescently-labeled growth cones.

However, foot processes can also be found on a larger "macro" scale, occupying relatively large areas of the cell membrane. [1] For example, microglia can use their primary processes to constantly monitor and evaluate alterations in the brain environment, and they can further deploy thin filopodia from these primary processes to expand their surveillance area. [14]

Architectural similarities

The arborization and branching of foot processes are one of the features responsible for the structural and functional similarities among various cell types. [note 1] Podocytes and pericytes share many physiological properties due to their large surface areas and intricate network of primary and secondary processes that wrap around their associated capillaries. [15] [16]

In addition, foot processes of podocytes and dendritic extensions of neurons exhibit comparable morphological features, and molecular machinery as they both share similar proteins found at both synapses and foot processes, such as synaptopodin and dendrin. [17] This analogy between them is further supported by their shared vulnerability to pathological conditions such as Alzheimer's disease and minimal change nephropathy, both of which are characterized by reduction and damage of dendritic spines and foot processes respectively. [18]

Structure

The cytoskeleton

One key distinction between cellular processes and lamellipodia lies in the composition of their cytoskeletal elements. While cellular processes can be supported by any of the three major components of the cytoskeleton—microfilaments (actin filaments), intermediate filaments (IFs), or microtubules—, lamellipodia are primarily driven by the polymerization of actin microfilaments, not microtubules. [8] [19]

Microtubules are generally unable to generate the force required by lamellipodia for large-scale cell movement, as this requires a significant number of microtubules to reach the cell's leading edge in order to produce sufficient force to promote the development of significant protrusions and motility. As a result, lamellipodia are predominantly actin-based rather than microtubule-based. [19]

On the other hand, cellular processes can be:

  1. Radial microtubules: They are located in the proximal regions of the ramified processes of oligodendrocytes, that extend outward from the cell body.
  2. Lamellar microtubules: They are the microtubules that eventually wrap around the axon, forming the myelin sheath.

Numerous imaging methods, such as immunohistochemistry and fluorescence microscopy, have enabled the precise targeting of, and are currently used to identify, visualize and localize specific marker proteins in foot processes, such as GFAP and synaptopodin. Such techniques can be used to stain and study cells or identify relevant pathological changes. [8] [23]

3D-structured illumination microscopy (SIM) offers a powerful approach to visualizing the glomerular filtration barrier. By employing multiplex immunofluorescence staining for markers for podocytes (synaptopodin, nephrin), endothelial cells (EHD3), and components of the glomerular basement membrane (agrin), SIM provides high-resolution images comparable to those obtained through transmission electron microscopy. Gdz-0003-0019-g03.jpg
3D-structured illumination microscopy (SIM) offers a powerful approach to visualizing the glomerular filtration barrier. By employing multiplex immunofluorescence staining for markers for podocytes (synaptopodin, nephrin), endothelial cells (EHD3), and components of the glomerular basement membrane (agrin), SIM provides high-resolution images comparable to those obtained through transmission electron microscopy.
Confocal microscopy analysis of rat retinal sections immunolabeled for glial fibrillary acidic protein (GFAP) reveals distinct morphological changes in Muller cell foot processes. In normal retinas on the left, GFAP expression is predominantly localized to the innermost layers of the retina, namely the nerve fiber layer and the ganglion cell layer (GCL). However, on the right, there is a marked increase in GFAP-positive fibers, indicating pronounced hypertrophy and thickening of Muller cell processes. These hypertrophic processes extended through the inner nuclear layer (INL) and outer nuclear layer (ONL), strongly indicative of retinal gliosis (Nuclei, stained with DAPI, appear blue under microscopy). GFAP gliosis.jpg
Confocal microscopy analysis of rat retinal sections immunolabeled for glial fibrillary acidic protein (GFAP) reveals distinct morphological changes in Müller cell foot processes. In normal retinas on the left, GFAP expression is predominantly localized to the innermost layers of the retina, namely the nerve fiber layer and the ganglion cell layer (GCL). However, on the right, there is a marked increase in GFAP-positive fibers, indicating pronounced hypertrophy and thickening of Müller cell processes. These hypertrophic processes extended through the inner nuclear layer (INL) and outer nuclear layer (ONL), strongly indicative of retinal gliosis (Nuclei, stained with DAPI, appear blue under microscopy).

The mitochondria

In cells with unique architecture, energy requirements can vary significantly among different cellular compartments. As a result, mitochondria, within such cells, demonstrate a non-uniform distribution, and can be strategically localized in regions with the greatest energy needs. [24]

In order to support the substantial metabolic demands of neurovascular coupling, astrocytic endfeet are loaded and packed with elongated and branched mitochondria. [25] This represents a marked departure from the typical pattern, wherein mitochondria generally tend to become smaller as their distance from the cell body increases, particularly within the fine branches and branchlets. [26]

However, while fine astrocytic perisynaptic processes can only house the smallest mitochondria, perivascular endfeet present a notable exception, and they can accommodate significantly more complex and ramified mitochondria. [26] In cases of traumatic brain injury and subsequent blood-brain barrier disruption, there is even further augmentation in mitochondrial number and density within astrocytic endfeet in order to facilitate vascular remodeling as an adaptive response. [27]

On the contrary, foot processes of podocytes are devoid of mitochondria, and mitochondria are confined to the cytosol surrounding the nucleus. The absence of mitochondria in foot processes can be attributed to the apparent size disparity, since mitochondria are generally larger than foot processes (The diameter of foot processes of normal podocytes can be under 250 nm). [24] [28]

As a result, foot processes rely on glycolysis for their energy supply, which may be beneficial as glycolysis offers the advantage of being unrestricted by a maximum capacity. Mitochondria, on the other hand, have a maximal limit, that renders them incapable of generating additional energy upon increased demand. [24]

Energy requirements of foot processes of podocytes

Podocytes require a significant amount of energy to preserve the structural integrity of their foot processes, given the substantial mechanical stress they endure during the glomerular filtration process. [29]

Dynamic changes in glomerular capillary pressure exert both tensile and stretching forces on podocyte foot processes, and can lead to mechanical strain on their cytoskeleton. Concurrently, fluid flow shear stress is generated by the movement of glomerular ultrafiltrate, exerting a tangential force on the surface of these foot processes. [30]

In order to preserve their intricate foot process architecture, podocytes require a substantial ATP expenditure to maintain their structure and cytoskeletal organization, counteract the elevated glomerular capillary pressure and stabilize the capillary wall. [30]

It has also been suggested that podocytes may possess a reasonable degree of mobility along the glomerular basement membrane, a process that may also contribute to the high energy demand. Since filtered proteins may become entrapped and accumulate under podocyte cell body and major processes, a hypothesized strategy to facilitate the removal of these stagnant proteins involves a cyclical movement of podocytes, allowing trapped proteins to be dispersed from the subpodocyte space into the filtrate. [31]

Function

Foot processes are integral to the structure of diverse membranes and sheaths, and perivascular cells play a crucial role in the formation and maintenance of organ-blood barriers: [8] [32]

The interfaceAssociated foot processes
The blood-brain barrier and the blood-spinal cord barrier Pericytes and astrocytes endfeet (Astrocytic foot processes envelop the abluminal surface of brain capillaries, accounting for 70% to nearly 100% of their total surface area). [33]
The inner blood retinal barrier (iBRB) [34] Pericytes and foot processes of glial cells like astrocytes and Müller cells.
The glomerular filtration barrier Foot processes of podocytes.
The glia limitans Astrocytic endfeet.
The myelin sheath Oligodendrocytes.

Regulation of blood flow

Foot processes of certain mural cells possess the capability to regulate the diameter of their associated blood vessels. Through the processes of vasoconstriction and vasodilation, these cells can actively control the rate of blood flow by means of:

Vasoactive modulators, released from astrocytic endfeet, act on smooth muscle cells in arterioles, and pericytes in capillaries to regulate the vascular tone. BBB796.jpg
Vasoactive modulators, released from astrocytic endfeet, act on smooth muscle cells in arterioles, and pericytes in capillaries to regulate the vascular tone.

Barrier and permeability regulation

Podocytes, through their intricate network of foot processes, strictly control the passage of plasma proteins into the urinary ultrafiltrate. Podocytes establish a selective barrier between their foot processes, allowing only molecules of appropriate size and charge to traverse. The negatively charged glycocalyx coating the foot processes facing the urinary space further enhances this barrier, creating an electrostatic repulsion that impedes the filtration of albumin. [36]

Glomerular podocytes possess a diverse array of surface-expressed proteins that contribute to the selective filtration of solutes across the glomerular barrier, thereby maintaining fluid homeostasis within the body. Podofun.jpg
Glomerular podocytes possess a diverse array of surface-expressed proteins that contribute to the selective filtration of solutes across the glomerular barrier, thereby maintaining fluid homeostasis within the body.

Uptake and flux of ions, water and nutrients

Astrocytic foot processes are rich in:

Cellular interaction

Osteocytes

Bone vascularization is a metabolically demanding process, requiring substantial energy to support the proliferation and migration of endothelial cells. As a result, transcortical vessels (TCVs), which arise from the bone marrow, and then pass through the cortical (outer) layer of bone, require a robust supply of mitochondria to facilitate vascular development. [40]

Osteocytes, the most common cell type within mature cortical bone, actively participate in the growth and maintenance of TCVs through the transfer of mitochondria to endothelial cells. Scanning electron microscopy (SEM) images have revealed that osteocytes possess numerous dendritic processes with expanded, endfoot-like structures. These endfeet directly abut and communicate with TCVs, establishing a close physical association that enables the transfer of mitochondria, and thereby provide the endothelial cells with the energy necessary for vascularization. [40]

This SEM image illustrates the communication between osteocytes (Ocy) and transcortical vessels (TCV) via their endfeet (yellow arrows) to facilitate mitochondrial transfer. TCVs654.jpg
This SEM image illustrates the communication between osteocytes (Ocy) and transcortical vessels (TCV) via their endfeet (yellow arrows) to facilitate mitochondrial transfer.

Pericytes

While chemical signalling pathways have long been recognized as key mediators of intercellular communication, recent studies have highlighted the significance of direct physical interactions in facilitating coordinated cellular responses. For example, pericyte secondary processes establish contact with endothelial cells, resulting in the formation of peg-socket invaginations, where pericyte processes extend inward, forming indentations within the endothelial cell membrane. [15]

During the process of angiogenesis, newly formed microvessels typically consist of rapidly dividing endothelial cells and an immature basement membrane. Subsequent maturation of these microvessels involves the recruitment of pericytes. The presence of pericytes surrounding blood vessels is often associated with the inhibition of endothelial cell proliferation and the stabilization of newly formed microvessels. [41]

In diabetic retinopathy (DR), accumulation of toxic substances such as advanced glycation end-products (AGEs) leads to pericyte loss, weakening of capillary walls, and microaneurysms, all are hallmarks of DR. Abnormal changes in pericyte mechanical stiffness can impair their ability to maintain the arrest of capillary endothelial cell growth, which may be involved in angiogenesis, neovascularization, and proliferative DR. [42]

Cytotoxic T cells

Traditionally, CD8+ T-cells, responsible for combating intracellular pathogens, are required to undergo a multi-step migration process to reach infected organs. This process involves rolling along the endothelial surface, firm adhesion to the endothelium, and subsequent extravasation into the surrounding tissue. Nevertheless, in the liver, the fenestrated endothelium of hepatic sinusoids allows for direct contact between CD8+ T-cells and the hepatocytes. [43]

In case of viral or bacterial infection of hepatocytes, platelets have been observed to form clusters within the sinusoids of the liver and adhere to the surface of infected Kupffer cells. This aggregation is believed to serve as a mechanism for trapping pathogens and promoting their elimination by the immune system. [43]

CD8+ T-cells, encountering platelet aggregates within liver sinusoids, are arrested and actively migrate along these sinusoids. They stretch out foot processes through the sinusoidal pores into the space of Disse, and then scan hepatocytes for detection of infected cells. [note 2] Upon recognition of antigens, these T cells initiate a cytotoxic response characterized by producing cytokines and killing infected cells without the need for extravasation into the liver parenchyma. [43]

Microglia

Microglia, while primarily known for their immunological functions, exhibit remarkable plasticity, enabling them to perform a diverse range of roles within the central nervous system. Traditionally, microglia have been characterized as existing in two distinct morphological states that correlate with changes in their functional properties: [44]

The ramified stateThe amoeboid state
MorphologyMicroglia are extensively branched with numerous primary and secondary processes.Microglia are rounded with compact cell body and retracted processes.
Physiological functionsThey scan the central nervous system, and establish contacts with neurons, astrocytes and blood vessels.Exhibiting a high degree of motility, they migrate to the lesion site and demonstrate a potent phagocytic capacity for the clearance of debris and the elimination of pathogens.
Ramified microglia in a rat cortex before traumatic brain injury. Mikroglej 1.jpg
Ramified microglia in a rat cortex before traumatic brain injury.
Amoeboid microglia after traumatic brain injury. Makrofagi 2.jpg
Amoeboid microglia after traumatic brain injury.

Clinical significance

Foot process effacement

Foot process effacement (FPE) is a pathological condition, where foot processes of podocytes withdraw from their usual interdigitating position, retract into the primary processes of podocytes, and eventually fuse with the cell bodies, resulting in the formation of broad sheet-like extensions over the glomerular basement membrane (GBM). [45]

The podocyte cell bodies no longer maintain their typical position "floating" within the filtrate above the GBM. Instead, they become broadly adherent to it, resulting in the near-complete obliteration of the subpodocyte space, the region beneath the podocyte cell body and major processes. [45]

Effacement of foot processes (FP) of podocytes is evident in this scanning electron microscopy (SEM) image, enhanced with false coloring for improved visualization. Fpe2038.jpg
Effacement of foot processes (FP) of podocytes is evident in this scanning electron microscopy (SEM) image, enhanced with false coloring for improved visualization.

FPE occurs in all glomerular diseases, including minimal change disease (MCD), membranous nephropathy, diabetic kidney disease, and IgA nephropathy. FPE is hypothesized to be an adaptive mechanism in response to glomerular stress, rather than a mere consequence of cell injury and disease. [45]

For example, in inflammatory diseases such as anti-GBM glomerulonephritis, inflammatory mediators and the activation of the complement cascade can damage the attachment of the actin cytoskeleton in foot processes to the GBM, thereby increasing the risk of podocyte detachment from the GBM. [45]

As a result, podocytes undergo cytoskeletal reorganization, resulting in the formation of a robust, basal cytoskeletal network that is tightly adhered to the GBM in order to minimize the risk of podocyte detachment. Even in cases of extensive FPE, recovery from effacement is possible if the disease resolves or with therapeutic intervention, and podocytes can restore their foot processes to their normal interdigitating state. [45]

Staphylococcus epidermidis infections

Staphylococcus epidermidis , a common bacterium found as a normal commensal on human skin, is a significant cause of hospital-acquired infections that are associated with the use of implanted medical devices like heart valves and catheters. [46]

This bacterium can reach the bloodstream as a contaminant from the skin, and it adheres to the aforementioned implanted devices using various mechanisms. In addition to producing a slimy substance, S. epidermidis can anchor itself to the surface of the implant using foot processes. [47] These projections extend from the bacterial cell wall and attach to the implant in linear arrangements, either singly or in multiples. [note 3]

Aquaporin-4

Neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease characterized by the presence of serum antibodies directed against the water channel protein aquaporin-4 (AQP-4). These antibodies initiate a complement-dependent inflammatory cascade, culminating in tissue damage and destruction. [48] [49]

Given that AQP4 is primarily expressed on perivascular astrocytic foot processes in the spinal cord and by Müller cells in the retina, NMOSD preferentially affects the spinal cord, and the anterior visual system. [48]

Patients with NMOSD typically exhibit worse visual acuity compared to those with multiple sclerosis (MS), because NMOSD is primarily an inflammatory process targeting astrocytes, with demyelination as a secondary consequence. In contrast, MS primarily involves inflammatory demyelination. [49]

Since NMOSD targets Müller cells, which provide trophic support to the retina, and have a heightened expression of AQP4 in their foot processes facing blood vessels, it is evident that NMOSD can have a more severe impact on visual acuity. [49]

Alzheimer's disease

AQP-4 exhibits a polarized distribution in astrocytes, with a 10-times higher concentration in astrocytic endfeet, which are in contact with blood vessels, compared to non-endfoot regions. [39]

In contrast to the lateral membranes of numerous epithelial cell types, astrocyte lateral membranes are devoid of tight junctions, that prevent diffusion of membrane molecules. In order to maintain their polarization and orientation towards blood vessels, AQP-4 channels must be securely anchored by specialized proteins. [39]

Recent studies have revealed a correlation between multiple neurological disorders, and the loss of AQP4 polarity (i.e. when AQP4 are widely distributed throughout the astrocyte, instead of its typical localization at the endfeet). [50]

AQP-4 facilitates the flow of cerebrospinal fluid through the brain parenchyma from para-arterial to para-venous spaces, and thus AQP4 channels facilitate the clearance of waste products from the brain, thereby preventing their accumulation. [note 4] In Alzheimer's disease (AD), a disruption in the polarity of AQP4 can cause a buildup of waste products, such as amyloid beta and tau proteins, a defining characteristic of AD. [50]

This also explains why patients with NMSOD are at higher risk of developing AD, since damage of AQP4 in NMSOD may impair clearance of amyloid-beta. [51]

Epiretinal membrane

An epiretinal membrane (ERM) is an eye disease, where a greyish semi-translucent membrane progressively grows over the macula, leading to decreased visual acuity, metamorphopsia, and other complaints. ERM commonly occurs due to posterior vitreous detachment, which can cause a tear in the internal limiting membrane (ILM), allowing microglial cells to migrate through the disrupted retinal architecture and interact with other cells at the vitreo-retinal interface, ultimately contributing to the formation of ERM. [52]

The standard surgical treatment for symptomatic ERMs is pars plana vitrectomy with membrane peel. However, despite the apparent complete removal of the ERM, there remains a risk of recurrence, which can be attributed to the presence of residual microscopic ERM remnants and the potential role of Müller cell footplates in the internal limiting membrane (ILM) in facilitating further cell proliferation and membrane formation. Minimising recurrence can therefore be achieved through peeling the underlying ILM together with the ERM. [53]

However, ILM peeling may result in the unintended damage of Müller cells, thereby increasing the risk of complications such as development of dissociated optic nerve fiber layer (DONFL), probably due to trauma to Müller cell footplate, and concomitant alterations in the nerve fiber layer and ganglion cell layer. As a result, intraoperative optical coherence tomography (iOCT)-guided ERM removal is an alternative approach that may minimize the risk of recurrence without the need for routine ILM peeling. [53]

Notes

  1. ↑ This figure illustrates that foot processes of different cells can be considered analogous structures.
  2. ↑ This figure illustrates the formation of foot processes of CD8+ T-cells upon encountering platelet aggregates.
  3. ↑ This figure illustrates the foot processes that S. epidermidis use to anchor itself to the surface of the implant.
  4. ↑ This figure illustrates the mechanism of AQP-4 dysfunction in Alzheimer's disease.

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Chloride intracellular channel protein 5 is a protein that in humans is encoded by the CLIC5 gene.

<span class="mw-page-title-main">Tunneling nanotube</span> Biological structure

A tunneling nanotube(TNT) or membrane nanotube is a term that has been applied to cytoskeletal protrusions that extend from the plasma membrane which enable different animal cells to connect over long distances, sometimes over 100 μm between certain types of cells. Tunneling nanotubes that are less than 0.7 micrometers in diameter, have an actin structure and carry portions of plasma membrane between cells in both directions. Larger TNTs (>0.7 μm) contain an actin structure with microtubules and/or intermediate filaments, and can carry components such as vesicles and organelles between cells, including whole mitochondria. The diameter of TNTs ranges from 0.05 μm to 1.5 μm and they can reach lengths of several cell diameters. There have been two types of observed TNTs: open ended and closed ended. Open ended TNTs connect the cytoplasm of two cells. Closed ended TNTs do not have continuous cytoplasm as there is a gap junction cap that only allows small molecules and ions to flow between cells. These structures have shown involvement in cell-to-cell communication, transfer of nucleic acids such as mRNA and miRNA between cells in culture or in a tissue, and the spread of pathogens or toxins such as HIV and prions. TNTs have observed lifetimes ranging from a few minutes up to several hours, and several proteins have been implicated in their formation and inhibition, including many that interact with Arp2/3.

Neuroangiogenesis is the coordinated growth of nerves and blood vessels. The nervous and blood vessel systems share guidance cues and cell-surface receptors allowing for this synchronised growth. The term neuroangiogenesis only came into use in 2002 and the process was previously known as neurovascular patterning. The combination of neurogenesis and angiogenesis is an essential part of embryonic development and early life. It is thought to have a role in pathologies such as endometriosis, brain tumors, and Alzheimer's disease.

The blood–spinal cord barrier (BSCB) is a semipermeable anatomical interface that consists of the specialized small blood vessels that surround the spinal cord. While similar to the blood–brain barrier in function and morphology, it is physiologically independent and has several distinct characteristics. The BSCB is involved in many disorders affecting the central nervous system, including neurodegenerative diseases, pain disorders, and traumatic spinal cord injury. In conjunction with the blood–brain barrier, the BSCB contributes to the difficulty in delivering drugs to the central nervous system, which makes drug targeting of the BSCB an important goal in pharmaceutical research.

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