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A cKIT for Studying Primordial Germ Cells

“The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation”

Research into embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) has allowed a greater understanding of the development and differentiation of specific cellular lineages and the molecular mechanisms which control them. However, our lack of understanding of human foetal development translates to a lack of details to validate, guide and quality control differentiation in vitro. Germ cell development from pluripotent sources could aid research and therapeutics in human fertility (Hayashi et al, Ohinata et al and Reijo et al). Development is understood to begin in primordial germ cells expressing the tyrosine protein kinase receptor cKIT (see paper for extended references), but how these cells progress is relatively less understood, although widespread changes to epigenetic modifications are key to this process (Hajkova et al 2008, Hajkova et al 2010, Popp et al and Seki et al). Now, in a study from researchers from the laboratory of Amander T. Clark from the University of California, Los Angeles, USA, cKIT-positive PGCs have been tracked from 6 to 20 developmental weeks through the analysis of human embryonic and fetal samples allowing the identification of the temporal nature of alterations in multiple epigenetic modifications and, additionally, they show that established hESC lines are not equivalent to human PGCs (Gkountela et al).

Existence of Female Germline Progenitors in Doubt - “Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries”

Results of a recent study in Nature Medicine (White et al), backed up by other research of the last ten years, indicated that the understanding that oocytes in postnatal mammals cannot renew and their number is fixed (Telfer et al and Zuckerman) may be wrong (Johnson et al, Pacchiarotti et al, White YA et al, Zou et al 2009, Zou et al 2011). Most recently, using antibody-based separation techniques with the germ cell marker Ddx4, two groups have postulated the existence of functional female germline stem cells (FGSCs) and oogonial stem cells (OSCs) in adult mouse and human ovaries (White et al, Zou et al 2009, Zou et al 2011). However for many researchers, questions still remained unanswered about these potentially exciting findings. This led researchers from the laboratory of Kui Liua at the University of Gothenburg, Sweden to use an endogenous genetic approach in mouse to trace the proliferation and differentiation of Ddx4 cells in vitro and in vivo, finding that Ddx4-expressing cells in postnatal mouse ovaries do not proliferate and nor do they contribute to oocytes during de novo folliculogenesis (Zhang and Zheng et al).

Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells

From Cell
By Stuart P. Atkinson

Protocols for the differentiation of pluripotent stem cells to functional therapeutically relevant cells often give relatively low yield. However, new protocols from various groups have addressed this by going back to learn more about the in vivo development of the cell type or tissue that they wish to attain, and utilising this knowledge in new more advanced differentiation protocols which aim to increase yield. In vitro attempts to generate gametes or primordial germ cells in mouse and human (Area reviews in Daley and Saitou et al) have largely been based on the isolation of these cells from spontaneously differentiating embryoid body cultures, an inefficient method that generally does not derive sufficient cells for substantial analysis. Now, researchers from the group of Mitinori Saitou at Kyoto University, Japan have demonstrated the efficient generation of PGC-like cells in mice which have spermatogenic capability. By utilising what information is known regarding temporal and signalling dynamics during PGC development in vivo and in vitro, they have devised a new protocol which leads to the development of PGC-like cells over multiple stages which reflects the development of the epiblast in vivo. The major novel step is the conversion of mouse embryonic stem cells (mESCs) to epiblast-like cells (EpiLCs), a state which is highly similar to cells of the pregastrulating epiblast, but distinct from epiblast stem cells (EpiSCs), which are known to be competent to express Blimp1/Prdm1 and Prdm14 (Kurimoto et al, Ohinita et al, Vincent et al and Yamaji et al), two of the major regulators of PGCs. Importantly, these regulators mediate the generation of functional sperm after ex vivo induction by BMP4 and neonatal intratesticular transplantation (Saitou et al). This study is published in the August edition of Cell (Hayashi et al).

Germline stem cells: Public Row Ensues

Germline stem cells: Public Row Ensues

From Nature News

Recent correspondence in Nature has brought into question claims of the pluripotent nature of human adult germline stem cells (haGSCs) generated from human testicular tissue reported in 2008 from the lab of Thomas Skutella.   Read more in the Nature News article and read the correspondence and the authors reply, from Nature.

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