New Research shows how to make Human Stem Cell Lines divide equally

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by Amaris Castanon
For the first time, scientists have generated haploid embryonic stem (ES) cell lines in humans, as published in Nature. This could lead to novel cell therapies for genetic diseases – even color blindness (Benvenisty et al., 2016)
The study was performed by scientists from the Hebrew University of Jerusalem(Israel) in collaboration with Columbia University Medical Center (CUMC) and the New York Stem Cell Foundation (NYSCF).
The newly derived pluripotent, human ES cell lines demonstrated their ability to ‘self-renew’ while maintaining a normal haploid karyotype (i.e. without chromosomal breakdown after each generation) (Benvenisty et al., 2016).
While gamete manipulation in other mammalian species has yielded several ES cell lines (Yang, H. et al., Leeb, M. & Wutz, A.), this is the first study to report human cells capable of cell division with merely one copy of the parent’s cell genome (Benvenisty et al., 2016).
The genetic match between the stem cells and the egg donor may prove advantageous for cell-based therapies of genetic diseases such as diabetes, Tay-Sachs disease and even color blindness (Elling et al., 2011).
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Mammalian cells are considered diploid due to the fact that two sets of chromosomes are inherited: 23 from the father and 23 from the mother (a total of 46) (Wutz, 2014; Yang H. et al., 2013). Haploid cells contain a single set of 23 chromosomes and arise only as post-meiotic germ cells (egg and sperm) to ensure the right number of chromosomes end up in the zygote (embryo) (Li et al., 2014; Elling et al., 2011).
Other studies performed in an effort to generate ES cells from human egg cells reported generating solely diploid (46 chromosome) human stem cells, which is a problem (Leeb, M. et al., 2012; Takahashi, S. et al., 2014). This study, however, reported inducing cell division in unfertilized human egg cells (Benvenisty et al., 2016).
The DNA was labeled with a florescent dye prior to isolating the haploid stem cells and scattering (the haploid cells or the cells) among the larger pool of diploid cells. The DNA staining demonstrated that the haploid cells retained their single set of chromosomes, while differentiating to other cell types including nerve, heart, and pancreatic cells demonstrates their ability to give rise to cells of different lineage (pluripotency) (Benvenisty et al., 2016).
Indeed, the newly derived haploid ES cells demonstrated pluripotent stem cell characteristics, such as self-renewal capacity and a pluripotency-specific molecular signature (Benvenisty et al., 2016).
In addition, the group of researchers successfully demonstrated usage of their newly derived human ES cells as a platform for loss-of-function genetic screening. Therefore, elucidating the genetic screening potential of targeting only one of the two copies of a gene.
These findings may facilitate genetic analysis in the future by allowing an ease of gene editing in cancer research and regenerative medicine.
This is a significant finding in haploid cells, due to the fact that detecting the biological effects of a single-copy mutation in a diploid cell is difficult. The second copy does not contain the mutation and therefore serves as a ‘backup’ set of genes, making it a challenge for precise detection.
The newly derived haploid ES cells will provide researchers with a valuable tool for improving our understanding of human development and genetic diseases.
This study has provided scientists with a new type of human stem cell that will play an important role in human functional genomics and regenerative medicine.
References:
Derivation and differentiation of haploid human embryonic stem cells. Sagi I, Chia G, Golan-Lev T, Peretz M, Weissbein U, Sui L, Sauer MV, Yanuka O, Egli D, Benvenisty N. Nature. 2016 Apr 7;532(7597):107-11.

Elling, U. et al. Forward and reverse genetics through derivation of haploid mouse embryonic stem cells. Cell Stem Cell 9, 563–574 (2011).

Leeb, M. et al. Germline potential of parthenogenetic haploid mouse embryonic stem cells. Development 139, 3301–3305 (2012)

Leeb, M. & Wutz, A. Derivation of haploid embryonic stem cells from mouse embryos.Nature 479, 131–134 (2011)

Li, W. et al. Genetic modification and screening in rat using haploid embryonic stem cells. Cell Stem Cell 14, 404–414 (2014).

Takahashi, S. et al. Induction of the G2/M transition stabilizes haploid embryonic stem cells. Development 141, 3842–3847 (2014)

Wutz, A. Haploid mouse embryonic stem cells: rapid genetic screening and germline transmission. Annu. Rev. Cell Dev. Biol. 30, 705–722 (2014).

Yang, H. et al. Generation of genetically modified mice by oocyte injection of androgenetic haploid embryonic stem cells. Cell 149, 605–617 (2012)

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