Efficient Differentiation of Human Pluripotent Stem Cells to Endothelial Progenitors via Small-Molecule Activation of WNT Signaling

Lian, Xiaojun; Bao, Xiaoping; Al‐Ahmad, Abraham; Liu, Jialu; Wu, Yue; Dong, Wentao; Dunn, Kaitlin K.; Shusta, Eric V.; Palecek, Sean P.

doi:10.1016/j.stemcr.2014.12.011

Cited by 35 publications

(73 citation statements)

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“…However, even though they hold great promise for these therapeutic applications, iPSC-derived cells have yet to be developed to treat recalcitrant DFUs. Although it is now possible to differentiate many cell types from iPSCs such as fibroblasts, keratinocytes, endothelial cells, neurons, and adipocytes (21)(22)(23)(24)(25), which are critical for various stages of DFU healing, the differentiated phenotype and biologic potency of iPSC-derived cells has not been exploited for repair of chronic wounds.…”

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confidence: 99%

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

et al. 2018

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Diabetic foot ulcers (DFUs) are a major complication of diabetes, and there is a critical need to develop novel cell- and tissue-based therapies to treat these chronic wounds. Induced pluripotent stem cells (iPSCs) offer a replenishing source of allogeneic and autologous cell types that may be beneficial to improve DFU wound-healing outcomes. However, the biologic potential of iPSC-derived cells to treat DFUs has not, to our knowledge, been investigated. Toward that goal, we have performed detailed characterization of iPSC-derived fibroblasts from both diabetic and nondiabetic patients. Significantly, gene array and functional analyses reveal that iPSC-derived fibroblasts from both patients with and those without diabetes are more similar to each other than were the primary cells from which they were derived. iPSC-derived fibroblasts showed improved migratory properties in 2-dimensional culture. iPSC-derived fibroblasts from DFUs displayed a unique biochemical composition and morphology when grown as 3-dimensional (3D), self-assembled extracellular matrix tissues, which were distinct from tissues fabricated using the parental DFU fibroblasts from which they were reprogrammed. In vivo transplantation of 3D tissues with iPSC-derived fibroblasts showed they persisted in the wound and facilitated diabetic wound closure compared with primary DFU fibroblasts. Taken together, our findings support the potential application of these iPSC-derived fibroblasts and 3D tissues to improve wound healing.-Kashpur, O., Smith, A., Gerami-Naini, B., Maione, A. G., Calabrese, R., Tellechea, A., Theocharidis, G., Liang, L., Pastar, I., Tomic-Canic, M., Mooney, D., Veves, A., Garlick, J. A. Differentiation of diabetic foot ulcer-derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes.

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confidence: 99%

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

et al. 2018

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“…18 Furthermore, evidence reveals a close connection between the Notch signaling pathway, which is involved in regulating arterial marker expression, and canonical Wnt/b-catenin signaling. In fact, dual induction of NICD and b-catenin caused enhanced arterial gene expression during in vivo angiogenesis in adults.…”

Section: Discussionmentioning

confidence: 99%

“…18 Briefly, when hiPSC colonies reached approximately 80% confluence (day 1), the mTeSR medium was aspirated, and the wells were washed once with 1Â phosphate-buffered saline (PBS). Then, differentiation medium consisting of advanced Dulbecco's modified eagle medium (DMEM)/F12 supplemented with 2.5 mM GlutaMAX, and 60 mg/mL ascorbic acid (Sigma-Aldrich, A8960, St, Louis, MO, USA) as well as 10 mM CHIR99021 was added.…”

Section: D In Vitro Differentiation and Isolation Of Hipsc-ecsmentioning

confidence: 99%

“…17,18 The likely mechanism of endothelial specification and induction by CHIR is through the Wnt/bcatenin signaling pathway, in which b-catenin accumulates and travels to the nucleus to activate Wnt to target gene expression. 18 This protocol for the quick induction of EC progenitors from hiPSCs bypasses many of the limitations of previously published methods by significantly reducing differentiation time, avoiding fragile EB formation steps, and eliminating serum and growth factors from the differentiation medium completely.…”

Section: Introductionmentioning

confidence: 99%

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Engineered microvasculature in PDMS networks using endothelial cells derived from human induced pluripotent stem cells

et al. 2017

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In this study, we used a polydimethylsiloxane (PDMS)-based platform for the generation of intact, perfusion-competent microvascular networks in vitro. COMSOL Multiphysics, a finite-element analysis and simulation software package, was used to obtain simulated velocity, pressure, and shear stress profiles. Transgene-free human induced pluripotent stem cells (hiPSCs) were differentiated into partially arterialized endothelial cells (hiPSC-ECs) in 5 d under completely chemically defined conditions, using the small molecule glycogen synthase kinase 3b inhibitor CHIR99021 and were thoroughly characterized for functionality and arterial-like marker expression. These cells, along with primary human umbilical vein endothelial cells (HUVECs), were seeded in the PDMS system to generate microvascular networks that were subjected to shear stress. Engineered microvessels had patent lumens and expressed VE-cadherin along their periphery. Shear stress caused by flowing medium increased the secretion of nitric oxide and caused endothelial cells s to align and to redistribute actin filaments parallel to the direction of the laminar flow. Shear stress also caused significant increases in gene expression for arterial markers Notch1 and EphrinB2 as well as antithrombotic markers Kruppel-like factor 2 (KLF-2)/4. These changes in response to shear stress in the microvascular platform were observed in hiPSC-EC microvessels but not in microvessels that were derived from HUVECs, which indicated that hiPSC-ECs may be more plastic in modulating their phenotype under flow than are HUVECs.Taken together, we demonstrate the feasibly of generating intact, engineered microvessels in vitro, which replicate some of the key biological features of native microvessels.

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“…26 Activation of Wnt using CHIR99021 also promotes mesoderm differentiation that can lead to the high purity of cardiac lineage and endothelial lineage cells. 27 …”

Section: Wnt Agonists (Activators): Wnt Proteinsmentioning

confidence: 99%

Wnt-YAP interactions in the neural fate of human pluripotent stem cells and the implications for neural organoid formation

Bejoy

Song

2016

Organogenesis

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ABSTRACT. Human pluripotent stem cells (hPSCs) have shown the ability to self-organize into different types of neural organoids (e.g., whole brain organoids, cortical spheroids, midbrain organoids etc.) recently. The extrinsic and intrinsic signaling elicited by Wnt pathway, Hippo/Yesassociated protein (YAP) pathway, and extracellular microenvironment plays a critical role in brain tissue morphogenesis. This article highlights recent advances in neural tissue patterning from hPSCs, in particular the role of Wnt pathway and YAP activity in this process. Understanding the Wnt-YAP interactions should provide us the guidance to predict and modulate brain-like tissue structure through the regulation of extracellular microenvironment of hPSCs.

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Efficient Differentiation of Human Pluripotent Stem Cells to Endothelial Progenitors via Small-Molecule Activation of WNT Signaling

Cited by 35 publications

References 0 publications

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

Differentiation of diabetic foot ulcer–derived induced pluripotent stem cells reveals distinct cellular and tissue phenotypes

Engineered microvasculature in PDMS networks using endothelial cells derived from human induced pluripotent stem cells

Wnt-YAP interactions in the neural fate of human pluripotent stem cells and the implications for neural organoid formation

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