Sir
Studies using the multi-lineage progenitor (MLP) assay, which is an effective method to determine the developmental potential of individual progenitors towards the myeloid (M), and T- and B-cell lineages1,2,3, have enabled us to elucidate the process of lineage commitment in haematopoiesis. It has been hypothesized by many researchers that T-cell progenitors (p-T) and B-cell progenitors (p-B) are derived from haematopoietic stem cells (HSCs) through the bipotent stage of common lymphoid progenitors (CLPs; p-TBs in our terminology). As, using the MLP assay, p-TBs are not detected in fetal liver, whereas p-MTs and p-MBs are abundant, we speculated that the commitment of p-Ts and p-Bs occurs through p-MTs and p-MBs, respectively. Furthermore, we showed that the first lineage restriction from HSCs is the production of common myelo-erythroid progenitors (p-MEs) and common myelo-lymphoid progenitors (p-MTBs); p-MTBs are thought to be the main intermediate to form p-MTs and p-MBs4. In my Opinion article in Nature Reviews Immunology5, I proposed a new model of lineage commitment in haematopoiesis and reviewed previous articles in the light of this new concept.
Criticism of my opinion, as well as of our experiments, is given by M. Kondo and his colleagues (I. Weissman's group), who have published data supporting the existence of p-TBs6. Their comments can be summarized as follows: the culture system that is used by my group is unphysiological, and the data that are obtained retroactively in this system cannot be validated using in vivo reconstitution assays; and I have misinterpreted the data from Weissman's group.
I do not discuss the reliability of our experimental system here, because this was considered in my Opinion article5 and also in our previous papers1,2,3,4. The only point I would like to stress is that the cultivation of fetal thymic-organ cultures in 70% oxygen is no less physiological than the conditions of other culture systems. It is well known that organs that are submerged in liquid medium, being separated from a continuous blood supply, need more oxygen than is supplied by diffusion from normal air, and so fetal thymic-organ cultures are usually carried out at the air–liquid border7. The high-oxygen submersion culture was devised to improve this air–liquid border culture by maintaining the organ in medium, where it is easier to examine the role of exogenous agents8.
When a reinterpretation is made of previously published data from a new viewpoint, it is sometimes the case that the authors of the cited papers have difficulty in accepting alternative viewpoints. I am disappointed to receive these comments from Weissman and colleagues, and I feel that my intention has been completely misunderstood. I have not ignored the fact that CLPs were detected in bone marrow using the two-step clonal assay of Weissman's group6. My question is whether the CLP is the main intermediate stage in T- and B-cell lineage commitment, or whether p-MTs and p-MBs exist also during bone-marrow haematopoiesis. In my Opinion article, I mentioned only that the Cell paper from Weissman's group did not answer this question, because they have not ruled out the possibility of existence of p-MTs and p-MBs, which could be present in populations other than the CLP population.
The development of myelo-erythroid and T/B-lymphoid lineages has been studied in depth by many researchers, but the process of lineage commitment has not been described clearly. Both Weissman's group and my own group have made extensive efforts to relate the differentiation processes of myelo-erythroid, and T- and B-cell lineages, and I have always respected the work of Weissman's group. I would prefer a more constructive discussion, for example focusing on what can be deduced from data obtained from different experimental systems, rather than focusing on the problems associated with different systems. Haematopoiesis will be at the forefront of research on cell differentiation, but it is important that the process is described precisely for it to be useful in molecular analyses.
References
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Katsura, Y. Different approaches lead us to a new viewpoint. Nat Rev Immunol 2, 140 (2002). https://doi.org/10.1038/nri721-c2
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DOI: https://doi.org/10.1038/nri721-c2
