Small-Molecule Induction Promotes Corneal Epithelial Cell Differentiation from Human Induced Pluripotent Stem Cells

Mikhailova, Alexandra; Ilmarinen, Tanja; Uusitalo, Hannu; Skottman, Heli

doi:10.1016/j.stemcr.2013.12.014

Cited by 90 publications

(94 citation statements)

References 66 publications

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“…Cell replacement therapy using autologous or allogeneic adult limbal grafts has been the standard treatment for patients with severe limbal stem cell deficiency (LSCD) (Rama et al, 2010;Sangwan et al, 2011;Basu et al, 2016). However, in the case of bilateral epithelial defects and for the treatment of conditions affecting the stromal and endothelial cell layers, alternative stem cell sources such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been explored with a view to generating the various corneal cell types (Ahmad et al, 2007;Shalom-Feuerstein et al, 2012;Hayashi et al, 2012;Sareen et al, 2014;Mikhailova et al, 2014;Chan et al, 2013;Zhang et al, 2014;Chen et al, 2015;McCabe et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Generating minicorneal organoids from human induced pluripotent stem cells

et al. 2017

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Corneal epithelial stem cells residing within the annular limbal crypts regulate adult tissue homeostasis. Autologous limbal grafts and tissue engineered corneal epithelial cell sheets have been widely used in the treatment of various ocular surface defects. In case of bilateral limbal defects, pluripotent stem cell (PSC) derived corneal epithelial cells are now being explored as an alternative to allogeneic limbal grafts. We report here an efficient method to generate complex three dimensional corneal organoids from human PSCs. The eye field primordial (EFP) clusters that emerged from differentiating PSCs developed into whole eye ball-like, self-organized, three dimensional, miniature structures consisting of retinal primordia (RP), corneal primordia (CP), primitive eye lid-like outer covering and ciliary margin zone-like adnexal tissues in a step-wise maturation process within 15 weeks. These minicorneal organoids recapitulate the early developmental events in vitro and displayed similar anatomical features and marker expression profiles as that of adult corneal tissues and offers an alternative tissue source for regenerating different layers of the cornea and eliminates the need for complicated cell enrichment procedures.

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Section: Introductionmentioning

confidence: 99%

Generating minicorneal organoids from human induced pluripotent stem cells

et al. 2017

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“…Some significant efforts have already been made in these areas [2, 11]. Moreover, studies utilizing directed differentiation from iPS or ES cells to drive primitive cells to a lacrimal fate may require an understanding of the expression of genes in adult tissue [20]. …”

Section: Discussionmentioning

confidence: 99%

“…Directed differentiation experiments [20,30], in which immature stem cells are differentiated into mature cell types using changes in gene expression depend on a detailed understanding of critical developmental factors. Several studies have demonstrated the ability of stem cells to be differentiated into ectodermal cell types, but none have been reported on directing differentiation into lacrimal epithelial cells [20]. We believe a strong understanding of the differential gene expression and signaling pathway differences between lacrimal gland and other ectodermal tissue types will be critical in the advancement of stem cell methodologies to create lacrimal epithelium in vitro .…”

Section: Discussionmentioning

confidence: 99%

Human Lacrimal Gland Gene Expression

Aakalu

Parameswaran²,

Maienschein‐Cline

et al. 2017

PLoS ONE

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BackgroundThe study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development.MethodsWe performed global gene expression analysis of human lacrimal gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium.ResultsThe analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described.ConclusionsDifferential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas.

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“…This method utilizes a feeder layer and a differentiation medium [30]. Consequently, several groups followed similar protocols, most of them used Collagen type IV as coating material as this is the most abundant basement membrane component of the cornea [31–33]. Collagen type IV promotes the proliferation of p63-positive cells, a marker for corneal epithelial cells [34], though it is quite expensive.…”

Section: Discussionmentioning

confidence: 99%

Human induced pluripotent stem cell differentiation and direct transdifferentiation into corneal epithelial-like cells

Cieślar-Pobuda

Rafat²,

Knoflach

et al. 2016

Oncotarget

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The corneal epithelium is maintained by a small pool of tissue stem cells located at the limbus. Through certain injuries or diseases this pool of stem cells may get depleted. This leads to visual impairment. Standard treatment options include autologous or allogeneic limbal stem cell (LSC) transplantation, however graft rejection and chronic inflammation lowers the success rate over long time. Induced pluripotent stem (iPS) cells have opened new possibilities for treating various diseases with patient specific cells, eliminating the risk of immune rejection. In recent years, several protocols have been developed, aimed at the differentiation of iPS cells into the corneal epithelial lineage by mimicking the environmental niche of limbal stem cells. However, the risk of teratoma formation associated with the use of iPS cells hinders most applications from lab into clinics. Here we show that the differentiation of iPS cells into corneal epithelial cells results in the expression of corneal epithelial markers showing a successful differentiation, but the process is long and the level of gene expression for the pluripotency markers does not vanish completely. Therefore we set out to determine a direct transdifferentiation approach to circumvent the intermediate state of pluripotency (iPS-stage). The resulting cells, obtained by direct transdifferentiation of fibroblasts into limbal cells, exhibited corneal epithelial cell morphology and expressed corneal epithelial markers. Hence we shows for the first time a direct transdifferentiation of human dermal fibroblasts into the corneal epithelial lineage that may serve as source for corneal epithelial cells for transplantation approaches.

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Small-Molecule Induction Promotes Corneal Epithelial Cell Differentiation from Human Induced Pluripotent Stem Cells

Cited by 90 publications

References 66 publications

Generating minicorneal organoids from human induced pluripotent stem cells

Generating minicorneal organoids from human induced pluripotent stem cells

Human Lacrimal Gland Gene Expression

Human induced pluripotent stem cell differentiation and direct transdifferentiation into corneal epithelial-like cells

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