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Mammalian haploid stem cells: establishment, engineering and applications

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Abstract

Haploid embryonic stem cells (haESCs) contain only one set of genomes inherited from the sperm or egg and are termed AG- or PG-haESCs, respectively. Mammalian haESCs show genome-wide hypomethylation and dysregulated imprinting, whereas they can sustain genome integrity during derivation and long-term propagation. In addition, haESCs exhibit similar pluripotency to traditional diploid ESCs but are unique because they function as gametes and have been used to produce semi-cloned animals. More strikingly, unisexual reproduction has been achieved in mice by using haESCs. In combination with a gene editing or screening system, haESCs represent a powerful tool for studies of underlying gene functions and explorations of mechanisms of genetic and epigenetic regulation not only at the cellular level in vitro but also at the animal level in vivo. More importantly, genetically edited AG-haESC lines may further serve as an ideal candidate for the establishment of a sperm bank, which is a highly cost-effective approach, and a wide range of engineered semi-cloned mice have been produced. Here, we review the historical development, characteristics, advantages and disadvantages of haESCs. Additionally, we present an in-depth discussion of the recent advances in haESCs and their potential applications.

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Abbreviations

AG:

Androgenetic

CB:

Cytochalasin B

CNV:

Copy number variation

CRISPR:

Clustered, regularly interspaced short palindromic repeats

DKO:

Double knock-out

DMR:

Differentially methylated region

DNA:

Deoxyribonucleic acid

DNMT:

DNA methyltransferase

EB:

Embryoid body

ENU:

N-ethyl-N-nitrosourea

ESC:

Embryonic stem cell

FACS:

Fluorescence-activated cell sorting

GFP:

Green fluorescent protein

haESC:

Haploid embryonic stem cell

HCG:

Human chorionic gonadotropin

IAP:

Intracisternal A particle

ICAI:

Intracytoplasmic AG-haESC injection

ICM:

Inner cell mass

ICPI:

Intracytoplasmic PG-haESC injection

ICR:

Imprinting control region

ICSI:

Intracytoplasmic sperm injection

IG DMR:

Intergenic germline-derived DMR

LINE-1:

Long interspersed nuclear element-1

LTR:

Long terminal repeat

PB:

PiggyBac

PG:

Parthenogenetic

PGC:

Primordial germ cells

RGNNV:

Red-spotted grouper nervous necrosis virus

RRBS:

Reduced representation bisulfite sequencing

SGIV:

Singapore grouper iridovirus

SINE:

Short interspersed nuclear element

SMGT:

Sperm-mediated gene transfer

SNPs:

Single nucleotide polymorphisms

SNVs:

Single-nucleotide variations

SVCV:

Spring viremia of carp virus

TET:

Tet methylcytosine dioxygenase

TKO:

Triple knock-out

UHPLC-MRM-QQQ:

Ultra-high-performance liquid chromatography-multiple reaction monitoring triple quadrupole

2i:

GSK3βi and MEKi

2n ESC:

Diploid ESC

5mC:

5-Methylcytosine

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Acknowledgements

We would like to thank Mr. Ling Jin for the assistance in the schematics. This study was supported by grants from the National Key R&D Program of China (2016YFA0100400), the National Natural Science Foundation of China (31721003, 31871446 and 31801206), the Shanghai Rising-Star Program (19QA1409600) and China Postdoctoral Science Foundation (2018M640420).

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  1. Wenteng He and Jiayu Chen contributed equally to this work.

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  1. Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, China

    Wenteng He & Shaorong Gao

  2. Clinical and Translation Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Jiayu Chen & Shaorong Gao

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He, W., Chen, J. & Gao, S. Mammalian haploid stem cells: establishment, engineering and applications. Cell. Mol. Life Sci. 76, 2349–2367 (2019). https://doi.org/10.1007/s00018-019-03069-6

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