Adil MT , Simons CM , Sonam S , Henry JJ .

R01 EY023979 NEI NIH HHS

             wound healing

Xla Wt + Psoralen AMT + UV (Fig. 2 B C D E F, Fig. 4 A B C)
Xla Wt + Psoralen AMT + UV (Fig. 3 B C, Fig. 4 A-C)
Xla Wt + Psoralen AMT + UV (Fig. 5 G H)
Xla Wt + Psoralen AMT + UV (Fig. 6 A-D, Fig. S3, S4, S6, S7)
Xla Wt + Psoralen AMT + UV (Fig. 7 A A', Fig. S 5, Fig. S 8)
Xla Wt + Psoralen AMT + UV (Fig. 7 A, Fig. S 5)
Xla Wt + Psoralen AMT + UV (Fig. 7 B B', Fig. S 5, Fig. S 8)
Xla Wt + Psoralen AMT + UV (Fig. 7 B, Fig. S 5)
Xla Wt + Psoralen AMT + UV (Fig. 7 B, Fig. S 5)
Xla Wt + Psoralen AMT + UV (Fig. 7 C, Fig. S 5)
Xla Wt + Psoralen AMT + UV (Fig. 7 C, Fig. S 5)
Xla Wt + Psoralen AMT + UV (Fig. S 1)
Xla Wt + UV (Fig. 11 C)

	Fig. 1. Apparatus and procedure for the PUV treatment. (A) Standard 1 ml pipette tip, which is modified as (B) a special reservoir applicator pipette using a razor blade, according to the dimensions shown. The broad end of the pipette (mmc) is cut in half so that it can be attached to the metal rod held by the micromanipulator using a small binder clip. (C) Top view of the reservoir pipette showing the internal diameters (d1 and d2) of the pipette opening and side port or reservoir opening. (D–F) PUV-treatment procedure. (D) Anesthetized tadpole is placed in a petri dish on Kimwipes soaked in anesthetic solution. Reservoir pipette tip is affixed to a metal rod held by the micromanipulator using a small binder clip. The tip is gently placed around the cornea to form a sealed chamber. Psoralen solution is then added into the reservoir and allowed to contact the cornea. (E) Higher magnification view of area shown in panel D. (F) UV exposure using a 10X objective. UV is localized to the cornea, (bright blue spot), using the microscope iris diaphragm. (G) Schematic diagram of larval Xenopus eye. Structures are as labeled. cer, corneal end of reservoir; mmc, micromanipulator clamp end; ro, reservoir opening. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 2. Comparison of corneal phenotypes. Phenotypes in untreated control corneas (A, A′), PUV treated whole corneas (B-D, B′-D′), PUV treated half corneas (E, F, E′, F′), Psoralen only controls (whole cornea) (G, G′), and UV only controls (whole cornea) (H, H′). Images were taken at various time points (dpt), as indicated. (A, A′) Control cornea is clear and pigment cells are restricted to the edges of the peripheral cornea. (B, B′, C, C′) Cornea after PUV treatment starts showing increased opacity and vascularization (white arrows). Pigment cells (white arrowheads) are also entering the cornea. (D, D′) Cornea is still opaque 25dpt after whole cornea PUV treatment. The normal corneal phenotype is lost, and pigment cells completely cover the cornea (white arrowheads). (E, F, E′, F′) Dotted blue lines indicate the boundary between the PUV treated half and the untreated (control) half. (E, E′) At 15dpt after PUV treatment, the treated half shows opacity and increased pigmentation (white arrowheads), whereas the untreated half is devoid of pigment cells and appears transparent. (F, F′) At 28dpt after PUV treatment on half of the cornea, the treated half has become clear of pigment cells and the normal corneal phenotype and transparency are restored. (G, G′, H, H′) Psoralen only treated corneas and UV only treated corneas, respectively, are clear and pigment cells are restricted to the edges of peripheral cornea. Green arrowheads in (A′, E′ to H′) show transparent cornea. Blue arrowheads point to wrinkled irregular epithelium. an, anterior side of the tadpole; dr, dorsal side of the tadpole; ps, posterior side of the tadpole; vr, ventral side of the tadpole. Scale bar in H′ equals 500 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 3. Severe phenotypes in whole cornea PUV treated cases. PUV treated cases showing the more severe Stem Cell Deficiency (SCD) phenotypes. (A, A′) Control corneas depicting normal transparent cornea morphology. These corneas are free of vasculature, pigment cells, and the lateral line organs (white arrows) are restricted to the skin. (B, B′) PUV treated cases on the opposite sides of the control corneas shown in (A, A′) at 32 and 29 days post treatment, respectively, depicting the loss of the normal transparent corneal phenotype. The cornea is completely opaque and covered with epidermal tissue similar to that surrounding the eye. Skin cells, including pigment cells and the lateral line organs (white arrows), have invaded the corneal region. (C, C′) PUV treated cases at 15dpt, depicting vascularization with multiple blood vessels passing into the cornea (white arrowheads). an, anterior side of the tadpole; dr, dorsal side of the tadpole; ps, posterior side of the tadpole; vr, ventral side of the tadpole. Scale bar in C′ equals 200 μm for (C, C′), and 665 μm for (A, A′, B, B′).
	Fig. 4. Quantification of pigmentation, opacity, and vascularization following PUV treatment on whole corneas and half corneas. (A) Control corneas show very minimal levels of pigment cells (black line), whereas corneas that received PUV treatment show increased pigmentation at the corresponding time points (red line). (B) Control corneas show no opacity at all time points examined (silver columns), whereas opacity increased in PUV treated corneas as the time points progressed (orange and red columns). (C) A majority of control corneas showed no vascularization at all time points examined (silver columns), however, some corneas showed slight vascularization very close to the peripheral boundary of the cornea (gray columns). Vascularization scores in the PUV treated corneas increased as the time points progressed (orange and red columns). (D) In the cases where only half of the cornea received PUV treatment, the untreated half (blue line) shows minimal pigmentation, whereas the treated half (red line) shows an increase in pigmentation, through 15dpt, after which it starts declining as the pigment cells are lost from the cornea. (E) No corneal opacity was detected in the untreated half of the cornea (silver columns), whereas corneal opacity in the treated half of the cornea increased until 15dpt (orange and red columns), and then declined by 28dpt (blue column). (F) A majority of untreated halves of the corneas were scored 0 for vascularization at all time points examined (silver columns), however, some corneas showed slight vascularization very close to the peripheral boundary of the cornea (gray columns). Vascularization scores in the PUV treated corneas increased until 15dpt (orange and red columns), and then declined by 28dpt (blue and orange columns). Error bars represent standard error of the mean. Statistical analysis has been done for untreated control corneas vs. PUV treated corneas in (A), and for untreated control halves vs. the PUV treated halves of the corneas in (D). N = 7-12 for time points in (A–C), except for control (whole cornea) at 1dpt (N = 4). N = 5-9 for time points in (D–F). *** = p-value ≤ 0.0002. ** = p-value ≤ 0.008; * = p value ≤ 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 5. Tcf7l2 immunostaining showing appearance of Tcf7l2 expressing skin cells in the cornea region following whole cornea PUV treatments. (A–D) Normal skin tissue obtained from the flank region of a representative tadpole. (A) DIC image showing pigment cells, which are a characteristic of skin tissue. (B) Skin tissue shows positive immunostaining for Tcf7l2, which labels a subset of apical epithelial skin cells that are not normally present in the cornea. (C, D) are the corresponding Hoechst and merged images for (A, B), respectively. (E-H′) Control and PUV treated corneas obtained from the left and right sides of the same tadpole, respectively. (E, F) shows the peripheral epidermis region (skin that surrounds the cornea), where Tcf7l2 staining is normally observed. (E′, F′) shows the cornea region of the control (untreated) cornea, where no Tcf7l2 staining is normally observed. (G, H) is the peripheral skin region, and (G′, H′) is the cornea region overlying the eye and of a PUV treated cornea collected at 12dpt. The presence of Tcf7l2 expressing cells in the cornea region shows the presence of these skin cells. Note that these Tcf7l2 positive cells appear smaller and more compacted than those found in the surrounding skin. (F, F′, H, H′) are the corresponding merged (Tcf7l2+Hoechst) images of (E, E′, G, G′), respectively. Scale bar in D equals 100 μm and applies to A-D and equals 40 μm in H′ and applies to E-H’.
	Fig. 6. Quantification of pyknotic nuclei and apoptotic cell death following PUV treatment on whole corneas and half corneas. (A, B) Counts of pyknotic nuclei and TUNEL positive nuclei, respectively, in the untreated controls (whole cornea) (black line) and the PUV treated whole corneas (red line). (C, D) Counts of pyknotic nuclei and TUNEL positive nuclei, respectively, in the untreated (control) halves (blue line) vs. the PUV treated halves of the corneas (red line) of the same corneas. Control (whole cornea) from (A) has been included in (C) for convenience of comparison (black line). The observations have been taken at the time points indicated on the X-axis (dpt). The pyknotic nuclei and TUNEL positive nuclei are represented as a percentage of the total Hoechst nuclei. (A, C) Error bars represent standard error of the mean. (B, D) Boxes represent lower and upper quartiles; whiskers and outliers represent Tukey range. Statistical analysis has been done for untreated control corneas (black) vs. PUV treated corneas (red) in (A, B), and for untreated control halves (blue) vs. the PUV treated halves (red) of the corneas in (C, D). Outliers have been included in calculating p-values in (B, D). N = 9 for all time points in (A). N = 9-13 for time points in (B). N = 10 for all time points in (C). N = 10-15 for time points in (D). *** = p ≤ 0.001; ** = p ≤ 0.01; * = p ≤ 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 7. Quantification of p63 positive nuclei, mitosis, and total cell density following PUV treatment on whole corneas and half corneas. (A–C) Percentage of p63 positive nuclei, mitotic nuclei counts (H3S10), and total cell density, respectively, in the untreated controls (whole cornea) (black lines) vs. the PUV treated whole corneas (red lines). (A′-C′) Percentage of p63 positive nuclei, mitotic nuclei counts (H3S10), and total cell density in the untreated control half (blue lines) vs. the PUV treated half (red lines) of the cornea. The controls (whole cornea) from (A–C) have been included in (A′-C′), respectively, for convenience of comparison (black lines). The observations have been taken at the time points indicated on the X-axis, as days post treatment (dpt). Error bars indicate standard error of the mean. Statistical analysis has been done for untreated control corneas (black lines) vs. PUV treated corneas (red lines) in (A–C), and for untreated control halves (blue lines) vs. the PUV treated halves (red lines) of the corneas in (A′-C′). N = 7-10 for time points in (A). N = 10-15 for time points in (A′). N = 7-13 for time points in (B). N = 9-15 for time points in (B′). N = 9-13 for time points in (C). N = 10-15 for time points in (C′). *** = p ≤ 0.001; ** = p ≤ 0.01; * = p ≤ 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 8. Quantification of pigmentation in Psoralen only (whole cornea), UV only (whole cornea), and UV only (half cornea) controls. (A) The contralateral control corneas (black line) show a minimal level of pigmentation. Only slightly elevated levels of pigmentation were observed in Psoralen only whole cornea treatment controls (blue line). A significant increase was only observed at 7dpt. (B) When compared to the contralateral untreated corneas (black line), UV only treatment on whole corneas (red line) appears to cause a significant increase in the levels of pigmentation at 5, 7, and 15dpt. However, pigmentation was still minimal in the UV only treated controls at these time points. (C) In the cases where only half of the cornea received UV treatment, the treated halves (red line) show minimal increases in pigmentation at 1-7dpt. Error bars indicate standard error of the mean. Statistical analysis has been done for control cornea vs. Psoralen only treated (A), control cornea vs. UV only treated (B), and untreated halves vs. the UV only treated halves of the corneas (C). N = 4 for all time points in (A–C). *** = p ≤ 0.001; ** = p ≤ 0.01; * = p ≤ 0.05. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 9. Opacity and vascularization in Psoralen only (whole cornea), UV only (whole cornea), and UV only (half cornea) controls. Stacked column graphs of corneal opacity and vascularization are shown. For each time point examined, the analysis has been done for the Psoralen only treated control corneas vs. their contralateral corneas (A, D), respectively, the UV only treated control corneas vs. their contralateral corneas (B, E), respectively, and the untreated half vs. the treated half of the UV only half treated control corneas (C, F), respectively. None of the controls showed any signs of opacity at any of the time points examined (silver and blue columns in A, B, E). Whereas a majority of control specimens showed no signs of vascularization (silver and blue columns in D, E, F), some control specimens showed slight vascularization very close to the peripheral boundary of the cornea (gray and orange columns in D, E, F), however, these vessels never extended into the central cornea region. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 10. Quantification of pyknotic nuclei and apoptotic cell death in Psoralen only (whole cornea), UV only (whole cornea), and UV only (half cornea) controls. (A) Similar to the untreated control corneas (black line), both the Psoralen only controls (blue line) and the UV only controls (red line) showed minimal levels of pyknotic cell death at all time points examined. (B) Compared to the untreated control corneas (black line), the average percentage of TUNEL positive nuclei was lower in both the Psoralen only (blue line) and UV only (red line) controls at all time points. (C, D) At each time point, both the untreated halves (blue lines) and the UV only treated halves (red lines) of the corneas showed similar minimal levels of pyknosis (C), and apoptosis (D). The untreated controls (whole cornea) from (A, B) have been included in (C, D), respectively, for convenience of comparison. Error bars represent standard error of the mean. (B, D) Boxes represent lower and upper quartiles; whiskers and outliers represent Tukey range. Statistical analysis has been done for control (whole cornea) vs. Psoralen only treated, and control (whole cornea) vs. UV only treated in (A, B), and untreated halves vs. the UV only treated halves of the corneas in (C, D). Outliers have been included in calculating p-values in (B, D). N = 6-7 for Psoralen only, UV only, and UV only half treated corneas at all time points in (A–D). N = 9 for control (whole cornea) for all time points in (A–D). * = p ≤ 0.05 (displayed for UV only). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 11. Quantification of p63 positive nuclei, mitosis, and total cell density in Psoralen only (whole cornea), UV only (whole cornea), and UV only (half cornea) controls. At each time point observed, the percentage of p63 positive nuclei (A), and mitotic nuclei counts (B) were similar among the untreated controls (black line), Psoralen only controls (blue line), and UV only controls (red line), respectively. (C) Compared to the untreated controls (black line), the total cell density is significantly higher at 7 and 15dpt in Psoralen only controls (blue line), and significantly higher at all time points in UV only controls (red line). Percentage of p63 positive nuclei (A′), mitotic nuclei counts (B′), and total cell density (C′) in both the untreated (blue line) and treated (red line) halves of the UV only treated half cornea controls show similar levels, respectively. The controls (whole cornea) from (A–C) have been included in (A′-C′), respectively, for convenience of comparison. Error bars indicate standard error of the mean. Statistical analysis has been done for controls (whole cornea) vs. Psoralen only treated, and controls (whole cornea) vs. UV only treated in (A–C), and untreated halves vs. the UV only treated halves of the corneas in (A′-C′). N = 6-7 for Psoralen only treated, UV only treated, and UV only half treated at all time points in (A-C, A′-C′). N = 9 for controls (whole cornea) for all time points in (A, C, A′, C′). N = 7-9 for controls (whole cornea) for time points in (B, B′). *** = p ≤ 0.001; ** = p ≤ 0.01; * = p ≤ 0.05 (for UV only vs. controls (whole cornea)). # = p ≤ 0.05 (for Psoralen only vs. controls (whole cornea)). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
	Supplementary Fig. 1. (Fig. S1): Quantification of cornea area following PUV treatment on whole corneas. (supplements data in Fig. 2A–D, 2A′-2D′) Control corneas that received no PUV treatment show a steady increase in cornea area (black line). Corneas that received PUV treatment (red line) showed continued growth that was initially delayed compared to the control cornea. Error bars represent standard error of the mean. Statistical analysis has been done for untreated control corneas vs. PUV treated corneas. N = 7-12 for the time points, except for control cornea at 1dpt (N = 4). *** = p-value ≤ 0.0003. ** = p-value ≤ 0.005; * = p value ≤ 0.05.
	Supplementary Fig. 2. (Fig. S2): Histological examination of eye tissue morphology. (supplements data in Fig. 2A, C, 2D, 2A′, 2C′, 2D′) Representative images of Hematoxylin and Eosin stained eye cross sections are shown (Column i), along with the higher magnification images of their retina (Column iii) and ciliary marginal zones (Column ii and Column iv). (A, B) The untreated control and the PUV treated corneas, respectively, at 15 days post treatment (dpt). (C, D) The untreated control and the PUV treated cornea at 30dpt. No differences were observed in overall eye morphology between the untreated control and the PUV treated corneas, which includes the tissues of the retina and ciliary marginal zones. Scale bar in D column iv equals 50 μm for images in Column ii – Column iv, and 200 μm for images in Column i.
	Supplementary Fig. 3. (Fig. S3): Cell death analysis via pyknotic nuclei assessment following PUV treatment on whole corneas. (supplements the data in Fig. 6A) Representative images showing Hoechst staining for 1–5 days post treatment (dpt) as labeled. (A-C) and (A′-C′) correspond to 1-5dpt for untreated control corneas and PUV treated corneas, as indicated. (A-C) Control corneas show only a minimal number of pyknotic nuclei. (A′-C′) An increase in the number of pyknotic nuclei is observed at 1 and 3dpt in PUV treated corneas, after which the number of pyknotic nuclei is similar to control corneas at 5dpt. Red arrowheads indicate representative pyknotic nuclei. White dotted circles enclose single fragmented pyknotic nuclei. Scale bar in C′ is 50 μm.
	Supplementary Fig. 4. (Fig. S4): TUNEL assay for cell death analyses following PUV treatment on whole corneas. (supplements the data in Fig. 6B) Representative brightfield images of TUNEL positive nuclei are shown (Column i), alongside corresponding Hoechst images (Column ii), for the time points indicated as days post treatment (dpt). (A-D) and (A′-D′) correspond to 1, 3, 5, 15dpt for untreated control corneas and PUV treated corneas, as indicated. A significant increase in apoptosis levels in PUV treated corneas, as compared to control corneas was only observed at 1dpt. No significant differences were observed at other time points. Note presence of invading pigment cells in the PUV treated case shown in (D′). Red arrowheads indicate representative TUNEL positive nuclei and black arrows indicate pigment cells, which are larger and have a distinct color and irregular shape. Scale bar in D′ column ii is 50 μ
	Supplementary Fig. 5. (Fig. S5): Percentage of p63 positive nuclei, mitotic nuclei, and total cell density following PUV treatment on whole corneas. (supplements the data in Fig. 7A–C) Representative images of p63 positive nuclei are shown in the green fluorescence channel (Column i), mitotic nuclei (H3S10) are shown in the red fluorescence channel (Column ii), alongside corresponding Hoechst counterstain in the blue (UV) fluorescence channel (Column iii), for the time points indicated as days post treatment (dpt). (A-E) and (A′-E′) correspond to 1, 3, 5, 15, 25dpt for untreated control corneas and PUV treated corneas, as indicated. Percentage of p63 remains fairly consistent in untreated control corneas. PUV treatment reduced the percentage of p63 nuclei at 1dpt, and the nuclei appear damaged. The mitotic nuclei counts were decreased at 1dpt in PUV treated corneas, while an increase was observed in mitosis at 3 and 5dpt in the PUV treated corneas. After the initial increase, the mitotic counts declined at 15dpt to control levels, and remained lower than the mitotic counts in untreated control corneas at 25dpt. Total cell density remains fairly consistent from 1 to 15dpt in untreated control corneas, and an increase in the total cell density was observed at 25dpt. Total cell density decreased at 1dpt in PUV treated corneas, while increased total cell density was observed at 3, 5, 15, 25dpt. Scale bar in E′ column iii is 50 μm.
	Supplementary Fig. 6. (Fig. S6): Cell death analyses of pyknotic nuclei following PUV treatment on half corneas. (supplements the data in Fig. 6C) Representative images showing Hoechst staining for 1–5 days post treatment (dpt). (A-C) and (A′-C′) correspond to 1-5dpt for untreated control halves and PUV treated halves of the corneas, as labeled. (A-C) Untreated control halves shows a minimal number of pyknotic nuclei. (A′-C′) An increase in the number of pyknotic nuclei was observed at 1 and 3dpt in the PUV treated halves of the corneas, after which the number of pyknotic nuclei is similar to control halves of the corneas at 5dpt. Red arrowheads indicate representative pyknotic nuclei. White dotted circles enclose single fragmented pyknotic nuclei. Scale bar in C′ is 50 μm.
	Supplementary Fig. 7. (Fig. S7): TUNEL assay for cell death analyses following PUV treatment on half corneas. (supplements the data in Fig. 6D) Representative brightfield images of TUNEL positive nuclei are shown (Column i), alongside corresponding Hoechst images (Column ii), for the time points indicated as days post treatment (dpt). (A-D) and (A′-D′) correspond to 1, 3, 5, 15dpt for untreated control halves and PUV treated halves of the corneas, as indicated. An increase was observed in apoptosis at 1dpt in the treated half of the cornea vs. the untreated control half of the cornea, whereas no significant differences were observed at other time points. Red arrowheads indicate representative TUNEL positive nuclei. Scale bar in D′ column ii is 50 μ
	Supplementary Fig. 8. (Fig. S8): Percentage of p63 positive nuclei, mitotic nuclei, and total cell density following PUV treatment on half corneas. (supplements the data in Fig. 7A’-7C′) Representative images of p63 positive nuclei are shown in the green fluorescence channel (Column i), mitotic nuclei (H3S10) are shown in the red fluorescence channel (Column ii), alongside corresponding Hoechst counterstain in the blue (UV) fluorescence channel (Column iii), for the time points indicated as days post treatment (dpt). (A-E) and (A′-E′) correspond to 1, 3, 5, 15, 25dpt for untreated control half of the corneas and the PUV treated half of the corneas, as indicated. PUV treatment reduced the percentage of p63 nuclei at 1dpt in both the halves, which recovered at 15 and 25dpt. The treated half of the cornea initially showed a decrease in mitosis compared to the untreated half at 1dpt. Similar levels of mitosis were observed between the treated and untreated halves for 3, 5, 15, 25dpt, where both the halves showed an increase in mitosis at 3, 5, 25dpt. The total cell density in the treated half of the cornea, appeared similar to the untreated halves of these corneas for the respective time points, and showed an increase starting at 5dpt. Scale bar in E′ column iii is 50 μ

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