<i>Bmi1+</i> Progenitor Cell Dynamics in Murine Cornea During Homeostasis and Wound Healing

Kalha, Solja; Shrestha, Bideep; Sanz-Navarro, Maria; Klein, Ophir D.; Michon, Frédéric

doi:10.1002/stem.2767

Cited by 18 publications

(29 citation statements)

References 42 publications

(68 reference statements)

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“…3A). 54–60 Staining for each of these proteins was detected in clusters of cells in the basal regions of the limbus, and these clusters broadly correlated with regions where LaNt α31 staining was relatively enriched (Fig. 3A).…”

Section: Resultsmentioning

confidence: 88%

Differential Distribution of Laminin N-Terminus α31 Across the Ocular Surface: Implications for Corneal Wound Repair

Barrera

Troughton

Iorio

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Laminin N-terminus (LaNt) a31 is a relatively unstudied protein derived from the laminin a3 gene but structurally similar to netrins. LaNt a31 has, to date, been investigated only in two-dimensional (2D) keratinocyte culture where it influences cell migration and adhesion, processes integral to wound repair. Here we investigated LaNt a31 distribution in ocular surface epithelium, during limbal stem cell activation, and corneal wound healing.METHODS. Human, mouse, and pig eyes, ex vivo limbal explant cultures, and alkali burn wounds were processed for immunohistochemistry with antibodies against LaNt a31 along with progenitor cell-associated proteins. LaNt a31 expression was induced via adenoviral transduction into primary epithelial cells isolated from limbal explants, and cell spreading and migration were analyzed using live imaging.RESULTS. LaNt a31 localized to the basal layer of the conjunctival, limbal, and corneal epithelial cells. However, staining was nonuniform with apparent subpopulation enrichment, and some suprabasal reactivity was also noted. This LaNt a31 distribution largely matched that of keratin 15, epidermal growth factor receptor, and transformation-related protein 63a (p63a), and displayed similar increases in expression in activated limbal explants. During active alkali burn wound repair, LaNt a31 displayed increased expression in limbal regions and loss of basal restriction within the cornea. Distribution returned to predominately basal cell restricted once the wounded epithelium matured. Cultured corneal epithelial cells expressing LaNt a31 displayed increased 2D area and reduced migration, suggesting a functional link between this protein and key wound repair activities.CONCLUSIONS. These data place LaNt a31 in position to influence laminin-dependent processes including wound repair and stem cell activation.

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Section: Resultsmentioning

confidence: 88%

Differential Distribution of Laminin N-Terminus α31 Across the Ocular Surface: Implications for Corneal Wound Repair

Barrera

Troughton

Iorio

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…To investigate the transcriptional profile of CD109 + and CD200 + cells, expression of putative LSC markers ΔNp63, ABCB5, C/EBPδ, BMI1, AXIN2, FZD7, CHD3, WNT7A, CK14, and CK15 [12,16,[39][40][41][42][43], corneal epithelial differentiation marker CK3 [44] and marker of proliferative cells Ki67 [45] was assessed by qRT-PCR.…”

Section: The Expression Of Lsc Markers In the Cd109 And Cd200 Positivmentioning

confidence: 99%

CD200 Expression Marks a Population of Quiescent Limbal Epithelial Stem Cells with Holoclone Forming Ability

et al. 2018

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One of the main challenges in limbal stem cell (LSC) biology and transplantation is the lack of definitive cell surface markers which can be used to identify and enrich viable LSCs. In this study, expression of 361 cell surface proteins was assessed in ex vivo expanded limbal epithelial cells. One marker, CD200 was selected for further characterization based on expression in a small subset of limbal epithelial cells (2.25% ± 0.69%) and reduced expression through consecutive passaging and calcium induced differentiation. CD200 was localized to a small population of cells at the basal layer of the human and mouse limbal epithelium. CD200 cells were slow cycling and contained the majority of side population (SP) and all the holoclone forming progenitors. CD200 cells displayed higher expression of LSCs markers including PAX6, WNT7A, CDH3, CK14, CK15, and ABCB5 and lower expression of Ki67 when compared to CD200 . Downregulation of CD200 abrogated the ability of limbal epithelial cells to form holoclones, suggesting an important function for CD200 in the maintenance and/or self-renewal of LSCs. A second marker, CD109, which was expressed in 56.29% ± 13.96% of limbal epithelial cells, was also found to co-localize with ΔNp63 in both human and mouse cornea, albeit more abundantly than CD200. CD109 expression decreased slowly through calcium induced cell differentiation and CD109 cells were characterized by higher expression of Ki67, when compared to CD109 subpopulation. Together our data suggest that CD200 expression marks a quiescent population of LSCs with holoclone forming potential, while CD109 expression is associated with a proliferative progenitor phenotype. Stem Cells 2018;36:1723-1735.

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“…Cells marked with K14 CreER or CAGG CreER were observed migrating centripetally from the limbus to the central cornea ( Amitai-Lange et al, 2015 ; Di Girolamo et al, 2015 ; Dorà et al, 2015 ; Richardson et al, 2017 , 2016 ). Bmi1 CreER+ can be used to label comparatively shorter-lived progenitor populations located in the central cornea ( Kalha et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Defining compartmentalized stem cell populations with distinct cell division dynamics in the ocular surface epithelium

2020

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Adult tissues contain label-retaining cells (LRCs) which are relatively slow-cycling and considered to represent a property of tissue stem cells (SCs). In the ocular surface epithelium, LRCs are present in the limbus and conjunctival fornix; however, the character of these LRCs remains unclear due to lack of appropriate molecular markers. Using three CreER transgenic mouse lines, we demonstrate that the ocular surface epithelium accommodates spatially-distinct populations with different cell division dynamics. In the limbus, long-lived Slc1a3CreER-labeled SCs either migrate centripetally toward the central cornea or slowly expand their clones laterally within the limbal region. In the central cornea, non-LRCs labeled with Dlx1CreER and K14CreER behave as short-lived progenitor cells. The conjunctival epithelium in the bulbar, fornix, and palpebral compartment is regenerated by regionally-unique SC populations. Severe damage to the cornea leads to the cancellation of SC compartments and conjunctivalization, whereas milder limbal injury induces a rapid increase of laterally-expanding clones in the limbus. Taken together, our work defines compartmentalized, multiple SC/progenitor populations of the mouse eye in homeostasis and their behavioral changes in response to injury.

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Bmi1+ Progenitor Cell Dynamics in Murine Cornea During Homeostasis and Wound Healing

Cited by 18 publications

References 42 publications

Differential Distribution of Laminin N-Terminus α31 Across the Ocular Surface: Implications for Corneal Wound Repair

Differential Distribution of Laminin N-Terminus α31 Across the Ocular Surface: Implications for Corneal Wound Repair

CD200 Expression Marks a Population of Quiescent Limbal Epithelial Stem Cells with Holoclone Forming Ability

Defining compartmentalized stem cell populations with distinct cell division dynamics in the ocular surface epithelium

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