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Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways.

ABSTRACT: One of the most exciting fields in biomedical research over the past few years is stem cell biology, and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development. Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome, the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns. In particular, the targeting of stem cell signaling pathways is opening up a new avenue for drug discovery. Aberrations in these pathways result in various diseases, including cancer, fibrosis and degenerative diseases. A number of drug targets in stem cell signaling pathways have been identified. Among them, WNT and Hedgehog are two most important signaling pathways, which are the focus of this review. A hedgehog pathway inhibitor, vismodegib (Erivedge), has recently been approved by the US FDA for the treatment of skin cancer, while several drug candidates for the WNT pathway are entering clinical trials. We have discovered that the stem cell signaling pathways respond to traditional Chinese medicines. Substances isolated from herbal medicine may act specifically on components of stem cell signaling pathways with high affinities. As many of these events can be explained through molecular interactions, these phenomena suggest that discovery of stem cell-targeting drugs from natural products may prove to be highly successful.

SUBMITTER: An SM

PROVIDER: S-EPMC4002899 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways.

An Songzhu Michael SM Ding Qiang Peter QP Li Ling-song LS

Acta pharmacologica Sinica 20130527 6

One of the most exciting fields in biomedical research over the past few years is stem cell biology, and therapeutic application of stem cells to replace the diseased or damaged tissues is also an active area in development. Although stem cell therapy has a number of technical challenges and regulatory hurdles to overcome, the use of stem cells as tools in drug discovery supported by mature technologies and established regulatory paths is expected to generate more immediate returns. In particula ...[more]

PMID: 23708555

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Project description:Differentiating cerebellar organoids can be challenging due to complex cell organization and structure in the cerebellum. Different approaches were investigated to recapitulate differentiation process of the cerebellum from human-induced pluripotent stem cells (hiPSCs) without high efficiency. This study was carried out to test the hypothesis that the combination of different signaling factors including retinoic acid (RA), Wnt activator, and sonic hedgehog (SHH) activator promotes the cerebellar differentiation of hiPSCs. Wnt, RA, and SHH pathways were activated by CHIR99021 (CHIR), RA, and purmorphamine (PMR), respectively. Different combinations of the morphogens (RA/CHIR, RA/PMR, CHIR/PMR, and RA/CHIR/PMR) were utilized, and the spheroids (day 35) were characterized for the markers of three cerebellum layers (the molecular layer, the Purkinje cell layer, and the granule cell layer). Of all the combinations tested, RA/CHIR/PMR promoted both the Purkinje cell layer and the granule cell layer differentiation. The cells also exhibited electrophysiological characteristics using whole-cell patch clamp recording, especially demonstrating Purkinje cell electrophysiology. This study should advance the understanding of different signaling pathways during cerebellar development to engineer cerebellum organoids for drug screening and disease modeling. Impact statement This study investigated the synergistic effects of retinoic acid, Wnt activator, and sonic hedgehog activator on cerebellar patterning of human-induced pluripotent stem cell (hiPSC) spheroids and organoids. The results indicate that the combination promotes the differentiation of the Purkinje cell layer and the granule cell layer. The cells also exhibit electrophysiological characteristics using whole-cell patch clamp recording, especially demonstrating Purkinje cell electrophysiology. The findings are significant for understanding the biochemical signaling of three-dimensional microenvironment on neural patterning of hiPSCs for applications in organoid engineering, disease modeling, and drug screening.

Dataset Information

Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways.

Publications

Stem cell signaling as a target for novel drug discovery: recent progress in the WNT and Hedgehog pathways.

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