Challenging Dogmas - Or How Much Evidence Is Necessary To Claim That There Is a Direct Developmental and Functional Link Between The Primordial Germ Cell (PGC) Lineage and Hematopoiesis?

• Published in: Blood 2013-11, Vol.122 (21), p.1215-1215
• Main Authors: Kucia, Magdalena, Maj, Magda, Mierzejewska, Kasia, Shin, Dong-Myung, Ratajczak, Janina, Ratajczak, Mariusz Z
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.1215.1215

The recent hot debate on the existence in bone marrow (BM) of developmentally early stem cells with broader specification challenged the hierarchy within the stem cell compartment in murine BM. Evidence has accumulated that hematopoietic stem cells (HSCs) can become specified from a population of migrating primordial germ cells (PGCs) during embryogenesis. In support of this intriguing possibility, HSCs and PGCs are highly migratory cells, and specification of the first primitive HSCs in yolk sac blood islands as well as the origin of definitive HSCs in the aorta–gonado–mesonephros (AGM) region are chronologically and anatomically correlated with the developmental migration of PGCs in extra- and intra-embryonic tissues. Furthermore, several papers have described the sharing of chromosomal aberrations between germline tumors and leukemias or lymphomas, which suggests their clonal origin. Moreover, our recent work demonstrated the presence of quiescent, small, Oct-4+Nanog+Sca-1+Lin–CD45– stem cells in adult murine BM that express several markers shared with migratory PGCs (Leukemia 2010;24:1450) and can be specified into the hematopoietic lineage (Exp.Hematology 2011;39:225). These cells were named very small embryonic-like stem cells (VSELs). The aim of our study was to test the hypothesis that VSELs are related to PGCs, which would support a potential developmental link between hematopoiesis and the germ line. We employed transmission electron microscopy (TEM), immunohistochemical staining, RQ-PCR analysis of mRNA and miRNA expression, gene array studies, and promoter methylation analysis to evaluate the expression of genes characteristic of PGC specification. We evaluated the expression of sex hormone receptors in VSELs and HSCs, and by direct in vitro and in vivo studies, we studied the effect of androgens and pituitary gonadotropins on proliferation and expansion of VSELs and HSCs. The TEM studies revealed VSELs to be small cells with a high nuclear/cytoplasmic ratio, euchromatin, and few mitochondria. VSELs isolated under steady-state conditions from BM highly express, at the mRNA and protein levels, genes involved in specification of the epiblast (e.g., Stella, Fragilis, Blimp1) in addition to genes involved in PGC specification, such as Dppa2, Dppa4, and Mvh, which characterize late-migratory PGCs. The expression of some of these genes has been confirmed at the protein level and at the promoter level to confirm chromatin structure characteristic of a