Table 1.
Pathological conditions and injuries, their effects on adhesion and their correlations with CNV.
Table 2.
Model objects and processes.
Figure 1.
Retinal structure, the retinal pigment epithelium, Bruch's membrane and the choriocapillaris.
Left large-scale: Structure of the outer retinal layers, the RPE and the CC. Right: Detail of the CC-BrM-RPE-POS complex. CC: choriocapillaris, BrM: Bruch's membrane, RPE: Retinal pigment epithelium, CC BaM: Basement membrane of the CC, OCL: Outer collagenous layer, EL: Elastin layer, ICL: Inner collagenous layer, RPE BaM: Basement membrane of the RPE (we abbreviate RPE BaM as RBaM), POS: Photoreceptor outer segment, PIS: Photoreceptor inner segment, ONL: Outer nuclear layer. Light purple shading indicates the location of the inner retina. Scale bars ∼10 µm.
Figure 2.
Adhesive interaction processes in the model retina.
Our model includes two types of cell-cell and cell-BrM adhesion: 1) labile adhesion and 2) junctional adhesion. Modeled labile adhesion represents cell-cell or cell-ECM labile adhesion in the absence of strong junctional structures (e.g., RPE-POS adhesion). Junctional adhesion combines labile adhesion at cell boundaries with plastic coupling (e.g., between neighboring cells or between BrM and cells). Plastic coupling simulates cytoskeletally-coupled junctional structures as breakable springs (see the Methods section in supplementary Text S3) that mechanically connect neighboring cells and also connect cells to BrM. Junctional adhesion represents biological epithelial or endothelial junctional adhesion or cell-ECM focal adhesion. In the model, a single junctional adhesion between RPE cells and BrM represents the complex biological adhesion between RPE cells and their basal laminae (RBaL), adhesion between the basal laminae and their basement membrane (RBaM) and adhesion between RBaM and BrM (inset). Modeled adhesion processes are: EC-EC and EC-BrM junctional adhesion; EC-RPE, EC-POS and EC-PIS labile adhesion; RPE-RPE and RPE-BrM junctional adhesion; RPE-PIS and RPE-POS labile adhesion; PIS-PIS, PIS-POS and POS-POS junctional adhesion. Key: BrM: Bruch's membrane, RPE: retinal pigment epithelium, RBaM: basement membrane of the RPE, RBaL: basal lamina of the RPE, POS: photoreceptor outer segment, PIS: photoreceptor inner segment.
Table 3.
Classification of CNV type based on Morphometric Weight.
Table 4.
(Temporal) Nomenclature for CNV.
Table 5.
Nomenclature for CNV dynamics.
Figure 3.
CNV Initiation probability dependence on key adhesion mechanisms.
3D plot of the regression-inferred CNV initiation probability (Pinit) vs. three key adhesion strengths using ten simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting RRp = RRl and RBp = RBl. Red corresponds to Pinit = 1 and purple to Pinit = 0. The black region at the top-front corner indicates the locus of normal adhesion. The three isosurfaces of CNV initiation probability correspond to Pinit = 0.25 (front), 0.5 (middle) and 0.75 (back). The five adhesion parameters and their (multi)linear combinations account for 88% of the observed variance in CNV initiation probability (adjusted R2 = 0.83). Regression predicts a minimum CNV initiation probability of 0.08 for normal adhesion, much higher than observed in either our simulations or experiments. For normal RPE-POS labile adhesion, moderate impairment of either RPE-RPE (RRp = RRl) or RPE-BrM (RBp = RBl) junctional adhesion increases the CNV initiation probability to ∼50%. Severe impairment of RPE-POS increases the CNV initiation probability to ∼50% even when both RPE-RPE and RPE-BrM are normal.
Figure 4.
Sub-RPE CNV dependence on adhesion.
3D plot of the regression-inferred average MW using 10 simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting RRp = RRl and RBp = RBl. The average MW shows the stalk cell locus even when CNV fails to initiate, so a region prone to ET1 CNV develops ET1 CNV only if CNV initiates. Red corresponds to MW = 1 and purple corresponds to MW = 0. The black region at the top-left corner indicates the locus of normal adhesion. MW = 1.0 for RPE-RPE junctional adhesion normal, RPE-BrM junctional adhesion severely impaired (weak) and RPE-POS labile adhesion normal. The three isosurfaces correspond to MW = 0.25 (back), 0.5 (middle) and 0.90 (front). The five adhesion parameters and their (multi)linear combinations account for 93% of the observed variance in average MW for all 108 adhesion scenarios (adjusted R2 = 0.89). Severe impairment of RPE-POS labile adhesion greatly reduces the MW, so ET1 CNV can only occur when RPE-POS labile adhesion is near normal. Scenarios with severe impairment of RPE-BrM junctional adhesion (RBp = RBl = 1), and normal RPE-POS labile adhesion are prone to ET1 CNV for a wide range of RPE-RPE junctional adhesion impairment (MW>0.95 for RRp = RRl>1.5). The red region with MW>0.9 has Pinit>0.8. We have rotated the axes from their orientation in Figure 3 to show the regions in the parameter space prone to ET1 CNV. To show the structure of the isosurfaces, we have rotated the axes relative to Figure 3.
Figure 5.
Sub-Retinal CNV dependence on adhesion.
3D plot of the regression-inferred average (1−MW) using 10 simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting RRp = RRl and RBp = RBl. The average (1−MW) shows the stalk cell locus even when CNV fails to initiate, so a region prone to ET2 CNV, develops ET2 CNV only if CNV initiates. Red corresponds to (1−MW) = 1 and purple corresponds to (1−MW) = 0. The black region at the top-back corner indicates the locus of normal adhesion. The three isosurfaces correspond to (1−MW) = 0.25 (right), 0.5 (middle) and 0.90 (left). The five adhesion parameters and their (multi)linear combinations account for 93% of the observed variance in average MW for all 108 adhesion scenarios (R2 = 0.89). The red region with (1−MW)>0.9, can be divided into three sub-regions: 1) When RPE-RPE junctional adhesion is normal, RPE-BrM junctional adhesion is moderately impaired, and RPE-POS labile adhesion is severely impaired (weak). 2) When RPE-RPE junctional adhesion is severely impaired (weak) and RPE-BrM junctional adhesion is normal, independent of RPE-POS labile adhesion. 3) When RPE-RPE adhesion is weak, RPE-BrM adhesion is moderately to severely impaired, and RPE-POS adhesion is severely impaired. The red region does not include all adhesion scenarios in Table S3 leading to Early Type 2 CNV. To show the structure of the isosurfaces, we have rotated the axes relative to Figure 3.
Figure 6.
Stable Type 1 CNV dependence on adhesion.
3D plot of the regression-inferred probability of occurrence of Stable Type 1 CNV (S11 CNV probability) using 10 simulation replicas for each adhesion scenario in the asymmetrically reduced parameter space obtained by setting RRp = RRl and RBp = 3 (indicated by the RPE-BrM* axis label). Red corresponds to a S11 CNV probability of 1 and purple corresponds to a S11 CNV probability of 0. The black region at the top-left corner indicates the locus of normal adhesion. The maximal regression-inferred probability of S11 CNV is 0.93 when RPE-RPE junctional adhesion is normal (RRp = RRl), RPE-BrM labile adhesion is severely impaired (RBl = 1), RPE-BrM plastic coupling is normal (RBp = 3), and RPE-POS labile adhesion is normal. The three isosurfaces correspond to S11 CNV probabilities of 0.25 (back), 0.5 (middle) and 0.8 (front). The five parameters and their (multi)linear combinations account for 76% of the observed variance in the probability of occurrence of S11 CNV (R2 = 0.67). Severe impairment of RPE-POS labile adhesion and RPE-RPE junctional adhesion greatly reduces MW, so S11 CNV can only occur when both adhesion strengths are near normal. To show the structure of the isosurfaces, we have rotated the axes relative to Figure 3.
Table 6.
Adhesion scenario classification based on early CNV type.
Figure 7.
Dynamics of stable Type 1 CNV (S11 CNV).
A) Total number of stalk cells vs. time. B) Total number of stalk cells confined in the sub-RPE space vs. time. C) Total number of stalk cells in contact with the POS (stalk cells in the sub-retinal space) vs. time. D) Total number of RPE cells vs. time. E) Total contact area between RPE cells and BrM vs. time. F) Total contact area between POS cells and BrM vs. time. The different colors represent the dynamics of 10 simulation replicas of the adhesion scenario (RRl = 3, RRp = 3, RBl = 2, RBp = 2, ROl = 3) (Table S5, adhesion scenario ID: 38). (A, B) CNV initiates in 9 out of 10 simulation replicas. All develop Early Type 1 CNV. CNV remains confined in the sub-RPE space during one simulated year (Stable Type 1 CNV). A Fully developed sub-RPE capillary network contains about 45 stalk cells (∼3000 cells/mm2). In 5 simulation replicas a few stalk cells die during the simulated year due to lack of RPE-derived VEGF-A. (C) Stalk cells have minimal contact with the POS. (D, E) The RPE remains viable and its total contact area with BrM decreases as stalk cells proliferate. (F) The POS never contacts BrM, indicating that the RPE does not develop any holes.
Figure 8.
Snapshots of a simulation replica with stable Type 1 CNV.
3D visualization of a simulation replica exhibiting Stable Type 1 CNV over one simulated year (adhesion scenario ID: 38, simulation ID: 902) (RRl = 3, RRp = 3, RBl = 2, RBp = 2, ROl = 3). Snapshots of the simulation at months 3 (A), 6 (B), 9 (C) and 12 (D). (A) Stalk cells (black arrows) invade the sub-RPE space through a hole (black outline arrow) in BrM (light blue outline arrow) that the tip cell opens during the first 24 hours. Brown outline arrow shows the RPE cells. Red outline arrow shows the CC (B, C) Stalk cells proliferate until they fill the sub-RPE space in month 9, after which proliferation slows down (D) The 45 stalk cells form a connected capillary network in the sub-RPE space. Cell type colors: 1) POS and PIS: light purple, 2) RPE: brown, 3) Stalk cells: green, 4) Vascular cells (CC): red, 5) BrM: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. POS, PIS and RPE cells are more transparent to show the underlying structures. See also Video S1.
Table 7.
Adhesion scenario classification based on CNV dynamics.
Figure 9.
Dynamics of sub-RPE to sub-retinal translocation (T12 Translocation).
A) Total number of stalk cells vs. time. B) Total number of stalk cells confined in the sub-RPE space vs. time. C) Total number of stalk cells in contact with the POS (stalk cells in the sub-retinal space) vs. time. D) Total number of RPE cells vs. time. E) Total contact area between RPE cells and BrM vs. time. F) Total contact area between POS cells and BrM vs. time. The different colors represent the results of 10 simulation replicas of the adhesion scenario (RRl = 3, RRp = 3, RBl = 1, RBp = 1, ROl = 1) (Table S6 adhesion scenario ID: 93). (A, B) CNV initiates in all replicas. By 3 months, most replicas form a developed sub-RPE capillary network composed of ∼20 to 40 stalk cells (∼1500 to 3000 cells/mm2). 8 replicas develop Early Type 1 (ET1) CNV. Only one replica shows Stable Type 1 (S11) CNV. Some stalk cells in most replicas die due to lack of RPE-derived VEGF-A. (C) Two replicas show Stable Type 2 (S22) CNV (Early (ET2) and Late Type 2 (LT2) CNV, black and dark red lines). 7 replicas show LT2 CNV. (D) The RPE remains viable in all replicas. (E) The contact area between the RPE and BrM decreases as either ET1 CNV or S11 CNV develops, and remains constant during ET2 CNV. RPE reattaches to BrM during T12 CNV. (F) The POS contacts BrM once, but the contacts area and duration are both small, so the RPE does not develop any persistent or substantial holes.
Figure 10.
Snapshots of a simulation replica showing sub-RPE to sub-retinal translocation (T12 Translocation).
3D visualization of a simulation replica exhibiting T12 CNV translocation during one simulated year (RRl = 3, RRp = 3, RBl = 1, RBp = 1, ROl = 1) (adhesion scenario ID: 93, simulation ID: 849). Snapshots of the simulation at months 3 (A), 5 (B), 9 (C) and 12 (D). (A) Stalk cells (solid black arrow) invade the sub-RPE space through a hole in BrM (black outline arrow) and form a capillary network. All stalk cells remain in the sub-RPE space during the first 3 months. A few vascular cells fill the hole in BrM (black outline arrow) to connect CNV capillaries to the CC (red outline arrow). Brown outline arrow shows an RPE cell. (B) Half of the stalk cells (black outline arrow) have crossed the RPE and transmigrated into the sub-retinal space, forming a new capillary network in the sub-retinal space. The black arrow shows a stalk cell in the sub-RPE space. (C) Most stalk cells have transmigrated into the sub-retinal space and the RPE has completely reattached to BrM (Figure 9E, dark green line). A few vascular cells of the CC have transmigrated into the sub-retinal space (red outline arrow) (D) The sub-retinal capillary network has fewer stalk cells than (C) since stalk cells that migrate into the retina far from the RPE die. Cell type colors: 1) POS and PIS: light purple, 2) RPE: brown, 3) Stalk cells: green (stalk cells in the sub-retinal space have lighter shading), 4) Vascular cells (CC): red, 5) BrM: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. POS, PIS and RPE cells are more transparent to show the underlying structures. See also Video S2.
Figure 11.
Dynamics of sub-RPE CNV to sub-retinal CNV progression (P13 Progression).
A) Total number of stalk cells vs. time. B) Total number of stalk cells confined in the sub-RPE space vs. time. C) Total number of stalk cells in contact with the POS (stalk cells in the sub-retinal space) vs. time. D) Total number of RPE cells vs. time. E) Total contact area between RPE cells and BrM vs. time. F) Total contact area between POS cells and BrM vs. time. The different colors represent the results of 10 simulation replica of the adhesion scenario (RRl = 1, RRp = 3, RBl = 1, RBp = 2, ROl = 3) (Table S7, adhesion scenario ID: 83). CNV initiates in all replicas and all develop ET1 CNV. A few stalk cells in most replicas die due to lack of RPE-derived VEGF-A. (C) Stalk cells cross the RPE and invade the sub-retinal space once the number of stalk cells in the sub-RPE space reaches ∼60 cells, which usually occurs within first two months after initiation. CNV progression to the sub-retinal space is complete around month 5. (D) The RPE remains viable in all replicas. (E) The contact area between the RPE and BrM decreases as ET1 CNV develops, and remains constant afterwards throughout LT3 CNV. (F) The POS contacts BrM a few times, but the contact area and duration are both small, so the RPE does not develop any persistent or substantial holes.
Figure 12.
Snapshots of a simulation replica showing sub-RPE CNV to sub-retinal CNV progression (P13 Progression).
3D and 2D visualizations of a simulation replica exhibiting P13 CNV progression during one simulated year (RRl = 1, RRp = 3, RBl = 1, RBp = 2, ROl = 3) (Table S7, adhesion scenario ID: 83, simulation ID: 515). Snapshots of the simulation at months 1 (A), 2 (B), 6 (C) and 12 (D). (A) Stalk cells (solid black arrow) invade the sub-RPE space through a hole in BrM (blue outline arrow) and form a capillary network. The vascular cells (black outline arrow) of the CC (red outline arrow) occupy the hole that the tip cell forms during the first 24 hours of the simulation, connecting the CNV capillaries to the CC. All stalk cells remain in the sub-RPE space during the first month of the simulation. (B) A few stalk cells (black outline arrow) cross the RPE into the sub-retinal space. (C) Additional stalk cells migrate into the sub-retinal space and form vascular cords (black outline arrow). (D) A 2D cross-section of the retina showing the hole in BrM. The stalk cells form a sub-RPE capillary network (black arrow) connected to a sub-retinal capillary network (black outline arrows). Two vascular cells connect the CC to the CNV capillaries through the hole in BrM. Cell type colors: 1) POS and PIS: light purple, 2) RPE: brown, 3) Stalk cells: green (stalk cells in the sub-retinal space have lighter shading), 4) Vascular cells (CC): red, 5) BrM: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. POS, PIS and RPE cells are more transparent to show the underlying structures. See also Video S3.
Figure 13.
Stable Type 2 CNV dependence on adhesion.
3D plot of the regression-inferred probability of occurrence of Stable Type 2 CNV (S22 CNV probability) using 10 simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting RRp = RRl and RBp = RBl. Red corresponds to a S22 CNV probability of 1 and purple corresponds to a S22 CNV probability of 0. The black region at the top-back corner indicates the locus of normal adhesion. The three isosurfaces correspond to S22 CNV probabilities of 0.25 (right), 0.5 (middle) and 0.9 (left). The five parameters and their (multi)linear combinations account for 89% of the observed variance in the probability of occurrence of S22 CNV in all 108 adhesion scenarios (adjusted R2 = 0.84 ). S22 CNV occurs primarily when RPE-RPE junctional adhesion is moderately to severely impaired, RPE-BrM junctional adhesion is normal or moderately impaired, independent of RPE-POS labile adhesion (red region with S22 CNV probability>0.9). The red region does not include all adhesion scenarios in Table S8 leading to S22 CNV. To show the structure of the isosurfaces, we have rotated the axes relative to Figure 3.
Figure 14.
Dynamics of stable Type 2 CNV (S22 CNV).
A) Total number of stalk cells vs. time. B) Total number of stalk cells confined in the sub-RPE space vs. time. C) Total number of stalk cells in contact with the POS (stalk cells in the sub-retinal space) vs. time. D) Total number of RPE cells vs. time. E) Total contact area between RPE cells and BrM vs. time. F) Total contact area between POS cells and BrM vs. time. The different colors represent the results of 10 simulation replicas of the adhesion scenario (RRl = 1, RRp = 1, RBl = 3, RBp = 3, ROl = 3) (Table S8, adhesion scenario ID: 16). (A, C) CNV initiates in all replicas and all develop ET2 CNV during the first three months of the simulation. All replicas exhibit S22 CNV. A few stalk cells in most replicas die due to lack of RPE-derived VEGF-A. (C) Few or no stalk cells reach the sub-RPE space. (D) The RPE remains viable in all replicas. (E) The contact area between the RPE and BrM does not change as S22 develops. (F) The POS contacts BrM a few times, but the contact area and duration are both small, so the RPE does not develop any persistent or substantial holes.
Figure 15.
Snapshots of a simulation replica showing stable Type CNV (S22 CNV).
3D visualization of a simulation replica showing S22 CNV in one simulated year (RRl = 1, RRp = 1, RBl = 3, RBp = 3, ROl = 3) (adhesion scenario ID: 16, simulation ID: 556). Snapshots of the simulation at months 1 (A), 2 (B), 6 (C) and 12 (D). (A) Stalk cells (solid black arrow) invade the sub-retinal space through a hole in BrM (black outline arrow) and form a partially developed capillary network (B). CNV finishes sub-retinal invasion around month 5 and remains in the sub-retinal space throughout LT2 CNV (C–D). A few vascular cells (A, black outline arrow) fill the hole in BrM to connect the CNV capillaries to the CC (red outline arrow). Brown outline arrow shows an RPE cell. Cell type colors: 1) POS and PIS: light purple, 2) RPE: brown (stalk cells in the sub-retinal space have lighter shading), 3) Stalk cells: green, 4) Vascular cells (CC): red, 5) BrM: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. POS, PIS and RPE cells are more transparent to show the underlying structures. See also Video S4.
Figure 16.
Dynamics of sub-retinal CNV to sub-RPE CNV progression (P23 CNV Progression).
A) Total number of stalk cells vs. time. B) Total number of stalk cells confined in the sub-RPE space vs. time. C) Total number of stalk cells in contact with the POS (stalk cells in the sub-retinal space) vs. time. D) Total number of RPE cells vs. time. E) Total contact area between RPE cells and BrM vs. time. F) Total contact area between POS cells and BrM vs. time. The different colors represent the results of 10 simulation replicas of the adhesion scenario (RRl = 1, RRp = 1, RBl = 1, RBp = 1, ROl = 1) (Table S9, adhesion scenario ID: 108). CNV initiates in all replicas and all develop ET2 CNV. A few stalk cells in most replicas die due to lack of RPE-derived VEGF-A. (B) Stalk cells cross the RPE and invade the sub-RPE space once the number of stalk cells in the sub-RPE space reaches ∼50 cells, which usually occurs during the first month after initiation. Stalk cells gradually invade the sub-RPE space during one simulated year. (D) Up to 30 RPE cells (30% of the total) die. The number of RPE cell deaths increases with the number of sub-RPE stalk cells. (E) The contact area between the RPE and BrM decreases as P23 CNV develops. (F) In all replicas the POS contacts BrM persistently and extensively, as the RPE develops substantial holes (see Figure 17).
Figure 17.
Snapshots of a simulation replica exhibiting sub-retinal CNV to sub-RPE CNV progression (P23 CNV).
3D and 2D visualization of a simulation replica forming P23 CNV in one simulated year (RRl = 1, RRp = 1, RBl = 1, RBp = 1, ROl = 1) (adhesion scenario ID: 108, simulation ID: 1080). Snapshots of the simulation at months 1 (A), 3 (B), 6 (C) and 12 (D). (A2-D2) Cross-sections of (A1-D1) parallel and adjacent to BrM, so stalk cells shown in (A2-D2) contact BrM. The black open circles (A1-2) at the top corner and outline back arrows (A1-2) at the location of the hole in BrM are guides to the eye to align A2 to A1. The alignment is consistent across all panels. (A) Stalk cells (solid black arrow) invade the sub-retinal space through the hole in BrM (A1-2, black outline arrows) that the tip cell form during the first 24 hours of the simulation and form a fully developed sub-retinal capillary network by month 1. (A2) Only a few stalk cells, mostly near the hole in BrM, invade the sub-RPE space during the first month. (B1, C1) The sub-retinal capillary network does not grow significantly. (B2, C2) Additional stalk cells invade the sub-RPE space. (D) More stalk cells invade the sub-RPE space, disrupting the RPE and causing a micro-tear (D1-2, black arrows). The POS contacts BrM at the location of the RPE tear. Cell type colors: 1) POS and PIS: light purple, 2) RPE: brown (stalk cells in the sub-retinal space have lighter shading), 3) Stalk cells: green (3D-visualized stalk cells in the sub-retinal space have lighter shading), 4) Vascular cells (CC): red, 5) BrM: light blue. Scale bars ∼50 µm. We have rendered the boundaries of individual cells in A1-D1 as semi-transparent membranes. POS, PIS and RPE cells are rendered more transparent to show the underlying structures. See also Video S5.
Figure 18.
Dynamics of stable Type 3 CNV (S33 CNV).
A) Total number of stalk cells vs. time. B) Total number of stalk cells confined in the sub-RPE space vs. time. C) Total number of stalk cells in contact with the POS (stalk cells in the sub-retinal space) vs. time. D) Total number of RPE cells vs. time. E) Total contact area between RPE cells and BrM vs. time. F) Total contact area between POS cells and BrM vs. time. The different colors represent the results of 10 simulation replicas of the adhesion scenario (RRl = 1, RRp = 1, RBl = 2, RBp = 2, ROl = 3) (Table S10, adhesion scenario ID: 53). (A, B, C) CNV initiates in all replicas and all replicas develop ET3 CNV. During the first month after initiation, stalk cells gradually invade both the sub-RPE space and the sub-retinal space, with more invading the sub-RPE space. Between months 1 and 2 about 30% of the sub-RPE stalk cells transmigrate into the sub-retinal space. After month 3, the number of sub-RPE stalk cells increases slowly, while the number of sub-retinal stalk cells remains constant. (E) During the first month of the simulation, the contact area between the RPE and BrM rapidly decreases as stalk cells invade the sub-RPE space. Between months 1 and 2, the contact area between the RPE and BrM rapidly increases as sub-RPE stalk cells transmigrate into the sub-retinal space. The contact area between the RPE and BrM slowly decreases after month 3 throughout the simulated year. (D) A few RPE cells die in most replicas. (F) In a few replicas the POS persistently contacts BrM, as the RPE develops small holes.
Figure 19.
Snapshots of a simulation replica exhibiting stable Type 3 CNV (S33 CNV).
3D and 2D visualization of a simulation replica developing S33 CNV in one simulated year (RRl = 1, RRp = 1, RBl = 2, RBp = 2, ROl = 3) (adhesion scenario ID: 53, simulation ID: 917). Snapshots of the simulation at months 1 (A), 2 (B), 6 (C) and 12 (D). (A2-D2) Cross-sections of (A1-D1). All cross-section planes in (A1-D1) panels defined by the two thick black lines in A1. (A) Stalk cells invade the sub-RPE space through a hole in BrM (A1-2, black outline arrows) that the tip cell form during the first 24 hours of the simulation. These stalk cells then form a fully developed sub-RPE capillary network. (A2) Only a few stalk cells (black arrow, A1-2) reach the sub-retinal space during the first month. (B1, C1) The sub-retinal and sub-RPE capillary networks do not grow significantly. (C2) A capillary (black arrows), enveloped by a bilayer of RPE cells, connects the sub-retinal space to the CC via the hole in BrM (D) Stalk cells disrupt the RPE, forming small holes in the RPE (D2, black arrow). The stalk cells at the location of the hole in the RPE (D2, black arrow) contact both the POSs and BrM. The black outline arrow shows sub-retinal stalk cells. Cell type colors: 1) POS and PIS: light purple, 2) RPE: brown, 3) Stalk cells: green, 4) Vascular cells (CC): red, 5) BrM: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells in A1-D1 as semi-transparent membranes. POS, PIS and RPE cells are rendered more transparent to show the underlying structures. See also Video S6.
Table 8.
Geometrical and transport parameters.
Table 9.
Field object names.
Table 10.
Labile adhesion parameters (contact energies).
Table 11.
Labile adhesion strengths (contact energies).
Table 12.
Plastic coupling strengths () links between cell-type pairs.