PLURIPOTENT EMBRYONIC STEM CELLS: AN OVERVIEW

Pluripotent embryonic stem cells (ESCs) are unique cell types derived from the inner cell mass of the blastocyst stage of embryos. These remarkable cells possess the ability to differentiate into any cell type in the body, making them a vital resource for regenerative medicine, developmental biology, and therapeutic applications.

Their pluripotency is a result of specific gene expression patterns and signaling pathways that maintain their undifferentiated state while providing the potential for differentiation into specialized cell types.

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Extrinsic signaling pathways governing stemness of pluripotent stem cells in mouse and human

Extrinsic signaling pathways governing stemness of pluripotent stem cells. Pluripotency and self-renewal characteristics of stem cells modulated by positive or negative regulation of SOX2, NANOG, and OCT3/4 by various signaling pathways in the nucleus of both mouse and human. (A) Mouse naïve pluripotency mainly controlled by LIF/STAT3, BMP4, Wnt/b-Catenin, and FGF4/ERK signaling pathways. LIF maintains pluripotency through binding to its receptor, gp130/LIFR, followed by activation of JAK/STAT3.

Phosphorylated STAT3 interacts with KLF4 and maintains the pluripotency through OCT3/4. BMP4/SMAD signaling controls core transcriptional TFs through interaction with KLF4. FGF4/ERK signaling promotes differentiation of mESCs through JNK/c-JUN and MEK/ERK pathways as downstream regulators. (B) Primed state of pluripotency in mEpiSCs, hESC, and hiPSCs is mainly controlled by FGF2/ERK and TGFb/Activin/Nodal pathways. FGF2 acts through PI3K/AKT, PLCg and MEK/ERK. TGF/SMAD pathway directly controls pluripotency through interaction with NANOG. IGF2 binding to IGF1R activates PI3K/AKT pathway and regulates stemness by interaction with SOX2. Inhibitors and activators of signaling pathways showed by red blunt-headed and dark blue arrows, respectively.

KEY CHARACTERISTICS OF PLURIPOTENT EMBRYONIC STEM CELLs

Unlimited Self-Renewal: ESCs can proliferate indefinitely in vitro while maintaining their pluripotent capabilities. This characteristic is crucial for their use in research and therapy, allowing for the generation of large quantities of cells.
Differentiation Potential: Under specific culture conditions, ESCs can be directed to differentiate into various cell lineages, including neurons, cardiomyocytes, and insulin-producing cells. This ability holds promise for cell replacement therapies in diseases such as Parkinson's, diabetes, and heart disease.
Genetic Stability: Pluripotent ESCs typically exhibit low rates of genetic mutations and chromosomal abnormalities, which is essential for their safe application in clinical settings

Recent advancements have also highlighted the potential of induced pluripotent stem cells (iPSCs), which are generated by reprogramming somatic cells back to a pluripotent state. This method circumvents some ethical issues associated with the use of ESCs derived from embryos.

SIGNALING PATHWAYS INVOLVED IN ESCs MAINTENANCE AND DIFFERENTIOTION

Pluripotent ESCs are regulated by various intrinsic and extrinsic factors. Key signaling pathways that govern their self-renewal and differentiation include:

LIF/STAT3 Pathway: Leukemia inhibitory factor (LIF) signaling through STAT3 promotes self-renewal and inhibits differentiation of ESCs.
Wnt/β-catenin Pathway: This pathway is involved in maintaining pluripotency and regulating the differentiation process of ESCs.
Nodal/Activin Signaling: These pathways play crucial roles in the maintenance of pluripotency and the initiation of mesodermal and endodermal differentiation.
FGF/ERK Pathway: Fibroblast growth factor (FGF) signaling, particularly through the ERK pathway, plays a critical role in regulating both pluripotency and differentiation.
TGF-β/SMAD Pathway: In human ESCs, TGF-β signals through SMAD proteins to regulate pluripotency-related genes such as Nanog.
PI3K/AKT Pathway: This pathway supports self-renewal by interacting with other signaling cascades, including LIF and FGF signaling.

THE KEY BIOMARKERS OF PLURIPOTENCY

The core transcription factors that regulate pluripotency in ESCs include:

Oct4 (Pou5f1): Essential for maintaining pluripotency, Oct4 acts as a gatekeeper for the pluripotent state. Its expression is tightly regulated, and it interacts with other factors to activate or repress target genes involved in self-renewal and differentiation.
Sox2: This factor works closely with Oct4 to regulate the expression of genes critical for maintaining pluripotency. Sox2 is essential for the self-renewal of ESCs; its absence leads to differentiation into trophoblasts.
Nanog: Nanog plays a pivotal role in sustaining pluripotency by repressing differentiation signals. Although not strictly required for the establishment of pluripotency, its presence enhances the stability of the pluripotent state.

Epigenetic modifications play a crucial role in establishing and maintaining pluripotency. These include: DNA Methylation, Histone Modifications and Chromatin Remodeling.

APPLICATIONS OF PLURIPOTENT ESCS

The unique properties of pluripotent embryonic stem cells make them a powerful tool in various fields:

Regenerative Medicine: ESCs have the potential to develop into functional tissues and organs, providing a solution for transplantation therapies.
Disease Modeling: Researchers can use ESCs to create disease models that help study the underlying mechanisms of various disorders.
Drug Discovery: Pluripotent ESCs serve as a platform for high-throughput screening of drugs, particularly for their effects on specific cell types.

(1) Weatherbee BAT, et al. Pluripotent stem cell-derived model of the post-implantation human embryo. Nature. (2023);622(7983):584-593.

(2) La Regina A, et al. Culturing pluripotent stem cells: State of the art,challenges and future opportunities. Current Opinion in Systems Biology, 28, 100364.

(3) Mossahebi-Mohammadi M, et al. FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency. Front Cell Dev Biol. (2020)18:8:79.

(4) Liu G, et al. Advances in Pluripotent Stem Cells: History, Mechanisms, Technologies, and Applications. Stem Cell Rev Rep. (2019)23;16(1):3–32.

(5) Kimbrel EA, Lanza R. Pluripotent Stem Cells: The Last 10 Years. Regen Med. (2016);11(8):831-847.

(6) Huang G, et al. Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network. Cell Mol Life Sci. (2015)17;72(9):1741–1757.

(7) Hackett CH, Fortier LA. Embryonic Stem Cells and iPS Cells: Sources and Characteristics. Vet Clin North Am Equine Pract. (2011);27(2):233-42.

PLURIPOTENT EMBRYONIC STEM CELLS BIOMARKER LIST

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You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Signaling Pathways	Product ref	Informations
Pluripotent Embryonic Stem Cells	PESC1H1	List infos

Species : Mus musculus (mouse)

Signaling Pathways	Product ref	Informations
Pluripotent Embryonic Stem Cells	PESC1M1	List infos

Species : Rattus norvegicus (rat)

Signaling Pathways	Product ref	Informations
Pluripotent Embryonic Stem Cells	*******	List In progress...

Species : Sus Scrofa (Pig)

Signaling Pathways	Product ref	Informations
Pluripotent Embryonic Stem Cells	*******	List In progress...

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