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Correspondence |
National Institute of Hematology and Immunology 1519, PO Box 424 Budapest Hungary
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Introduction |
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As it is known, until recently, most people believed that extraembryonic areas (yolk sac, allantois, body stalk) are the sites of origin even for definitive hemopoiesis, and the role of stem cell migration was widely accepted [1, 2].
In the last years, excellent authors working at the Embryological Institute in Nogent-sur-Marne, Paris, France, concluded that stem cells for definitive hemopoiesis arise, independently from extraembryonic sources, inside the animal embryo. Intraembryonic stem cells were identified as dense clusters developing in close association with the abdominal, ventral aortic endothelium, at first on its intravascular aspect, and later on in the surrounding paraaortic mesenchymal tissue, the splanchnopleural meoderm. It was suggested that the discovery is valid even for humans [3-4].
One of the difficulties to definitely prove the validity of these milestone-forming observations lies in the fact that extraembryonic and intraembryonic circulatory pathways fuse before the onset of abdominal aortic/paraaortic stem cell clusters, and so, aortic/paraaortic stem cells may originate from migrating extraembryonic cells, including primordial germ cells (see below). Quite recently, Dieterlen-Lièvre et al. traced back the origin of these cells to the presomite (animal) embryo, i.e., before blood circulation [5].
In the columns of STEM CELLS Auerbach et al. recently demonstrated that yolk sac hemopoietic stem cells of mice have greater reproductive capability than stem cells obtained from fetal liver, umbilical cord blood, or adult bone marrow: they are able to reconstitute adult immunocompromised animals, even when introduced in very small numbers, such as 100 cells/mouse [6].
In addition, primordial germ cells disturb the scene, because these cells originate extraembryonically (e.g., from allantois), migrate to the very same splanchnopleural area, and are able to initiate multilineage hemopoiesis [7]. Preliminary transplantation experiments indicated that in vitro expanded primordial germ cells can reconstitute lethally irradiated recipients.
The old imagination for a common precursor for hemopoietic stem cells and vascular endothelial cells, the elusive hemangioblast could be reconsidered. Maximow believed, already in 1909, that this possibility is valid for the embryonic period only. Intraaortic stem cell clusters were described by Maximow as well as by Dantschakoff [8, 9].
The apparent lack of expression of MHC class I and class II antigens on yolk sac stem cells was emphasized by Auerbach and it was suggested that yolk sac hemopoietic stem cells could be viewed as candidates for achieving long-term reconstitution of hemopoiesis across histocompatibility barriers [6].
In connection with this statement, allow me to refer to an old observation made 25 years ago [10]. Although direct evidence for any take of injected cells was lacking, a gradually developing full clinical and subtotal hematological recovery occurred in a 29-year old patient who suffered from severe chronic aplastic anemia since at least 15 months. She was transfusion-dependent and before the intervention the interval between single transfusions was four weeks long only. Her minimum hgb-level was 6.0 g/dl, reticulocytes were below 10,000/microl and she had 25,000 platelets/microl. Her blood cell counts did not improve during additional conventional therapy, including months-long prednisolone.
Sixteen months after the diagnosis, she became pregnant, and agreed to interrupt pregnancy. Daily 50 mg prednisolone was applied up to day 7 post-intervention, with gradually diminished doses for another 10 days. Hysterectomy was performed, so the embryo was fresh and intact. She had been treated with intravenous injection of 2.5 x 105 unprocessed yolk sac and 4.2 x 107 "liver" cells from her own 22 mm CR length 7-week old embryo.
Four weeks after the intervention, the hgb-level was 10 g/dl, with up to 150,000 reticulocytes, and the platelet count was 60,000/microl. No transfusion has been given to the patient since the intervention, and she remained free of complaints, and performed the same work as before her illness, now 25 years post intervention.
The role of yolk sac cells cannot be estimated. We did not succeed to demonstrate any subpopulation of donor cells, even years after the intervention. There was no similar case during the subsequent years. We applied fetal liver cells from own fetuses for two subsequent mothers suffering from severe aplastic anemia, without success. These fetal donors were, however, 17-and 19-weeks old.
Although it is extremely difficult to get fresh, intact human yolk sac, the stimulating paper by Auerbach et al. could induce some rebirth of interest. It would be of interest to know whether the telomeric length of chromosomes in yolk sac stem cells, with a short history of cell divisions, could allow a special proliferation potential across histocompatibility barriers [11]?
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