Jan 28, 2016 - In the study presented in this issue, Dahlin et al have precisely identified novel human. PB-derived cell populations giving rise only to CD117. +.
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28 JANUARY 2016
I VOLUME 127, NUMBER 4
l l l HEMATOPOIESIS AND STEM CELLS
Comment on Dahlin et al, page 383
Mast cell differentiation: still open questions? ----------------------------------------------------------------------------------------------------Michel Arock
ECOLE NORMALE SUPERIEURE DE CACHAN
In this issue of Blood, Dahlin et al report on a minor circulating human mast cell (MC) progenitor cell population (lineage-negative [Lin2]/CD34hi/CD117int/hi/ high-affinity immunoglobulin E receptor-positive [FceRI1]), with an immature MC-like appearance, which is present in the peripheral blood (PB) of healthy individuals and of asthma subjects well controlled by treatment or with reduced lung function.1
M
Cs are tissue-resident cells which do not circulate in their fully granulated state. They are involved in various physiological and pathological processes, either through direct cell-cell interactions or by their ability to release a myriad of mediators.2 Particularly, they play a pivotal role in allergic diseases which can be severe, including allergic asthma.3 Allergic reactions may be life-threatening in the case of anaphylactic shock, due to a devastating release by activated MCs of deleterious mediators harboring, among others, vasoactive, bronchoconstrictive, and/or proinflammatory effects.4 Interestingly, in humans, different populations of MCs are found, depending on their tissue location and their content of proteases. Specifically, 2 major types of MCs have been described: MCs containing only tryptase (MCT), mostly found in mucosal tissues, and MCs containing tryptase, chymase, and carboxypeptidase A (MCTC), particularly abundant in the serosal microenvironment.5 The identification of the ancestor of MCs is critical for understanding the underlying mechanisms of allergic disorders and hematologic diseases such as systemic mastocytosis. Possibly, such progenitors would be a novel drug target in MC-related diseases.
Although already described in 1879 by Paul Ehrlich, the origin of MCs has long been a matter of debate in humans. In a report from the early 1980s, the authors concluded that MCs might be derived from circulating monocytes.6 However, in the early 1990s it became clear that MCs derive from bone marrow (BM) CD341/FceRI2 progenitors which transiently circulate in the bloodstream as morphologically undifferentiated cells7 and that these cells, which are composed of a subset of circulating CD341/CD1171/ Ly2/CD142/CD172 cells,8 are capable of reaching various tissues for their final maturation steps. Additional investigations were conducted to further identify the circulating MC-committed progenitor(s) and, in 1999, a circulating human MC/monocyte mixed progenitor was described as a CD341/ CD1171/CD131/FceRI2 cell, which could give rise to MCs, monocytes, or mixed MC/monocyte colonies, depending on the culture conditions.9 However, even after this report, a population of distinct progenitor cells that gave rise only to MCs has remained undiscovered to date. In the study presented in this issue, Dahlin et al have precisely identified novel human
BLOOD, 28 JANUARY 2016 x VOLUME 127, NUMBER 4
PB-derived cell populations giving rise only to CD1171/FceRI1 MCs.1 Notably, they identified a minor circulating cell population (0.0053% of the isolated cells in PBs of healthy individuals) that can only develop into MCs and does not retain the ability to develop into monocytes. Indeed, a Lin2/CD34hi/ CD117int/hi/FceRI1 cell subset, expressing or not expressing CD13, gave rise to CD1171/ FceRI1 granulated tryptase-positive MCs at a high frequency (.70%). This frequency was far lower when the authors attempted to work with the FceRI2 cell subsets (the frequency of Lin2/CD34hi/CD117int/hi/FceRI2 cells giving rise to CD1171/FceRI1 tryptasepositive MCs is between 2.7% and 5.7%), meaning that acquiring the expression of FceRI by CD341/CD1171 cells commits them definitively to the MC lineage. Subsequently, the authors performed different maneuvers to further enrich the Lin2/CD34hi/ CD117int/hi/FceRI1 cell subset into even more MC-committed elements, by using exclusion of CD45RA1 cells and by further purification of cells expressing or not expressing CRTH2 (a PGD2 receptor) and/or integrin b7. However, the use of these 3 markers did not appear to increase the frequency of MC-committed progenitors. Of note, the authors analyzed the dividing capability of each of their MC-committed progenitors, as well as their potential to become fully granulated upon culture. They observed that the Lin2/CD34hi/CD117int/hi/FceRI1 or Lin2/CD34hi/CD117int/hi/FceRI1/ CD45RA2/CRTH22/integrin b71 cells have very low dividing capabilities, which was somewhat expected from a MC-committed progenitor already expressing FceRI at a high level. The vast majority of the progenitors were found to be capable of becoming fully granulated after 7 days in culture, a short time consistent with the hypothesis that the progenitors identified in the present study are already highly committed to the MC lineage and might represent more of a “promastocyte”
373
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subtypes,10 it would be important to evaluate whether MCs that arise from the committed precursor identified here express a full range of MC proteases. In addition, one can question whether, due to their poor capability to divide, those progenitors are “the” MC-committed progenitors or a very late “promastocyte.” To conclude, despite the increasing information accumulating in the field, there is still plenty of room for “mastomaniac” researchers to further investigate the numerous hierarchical steps leading from the uncommitted pluripotent hematopoietic progenitors to the mature tissue-resident MCs. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES
Proposed scheme of the major steps of differentiation of MCs from uncommitted hematopoietic progenitors. Based on the current knowledge and on the data presented in this issue by Dahlin et al,1 it can be postulated that CD341/CD1171 BM uncommitted hematopoietic progenitors, which express neither CD13 nor FceRI, can give rise to early committed circulating mixed MC/monocyte CD341/CD1171 progenitors, which express CD13, but are still FceRI2. Upon different culture conditions, these mixed progenitors can produce pure MC colonies, colonies containing only monocytes, or mixed MC/monocyte colonies. These CD131 progenitors can further acquire the expression of FceRI, as described by Dahlin et al. At this step, the progenitors are definitively committed to the MC lineage and may reach various tissues to acquire the corresponding mature phenotype, that is, a MCT phenotype in mucosal tissues and a MCTC phenotype in serosal tissues. Alternatively, also based on the present report, it can be postulated that CD341/CD1171/CD132/ FceRI2 BM uncommitted hematopoietic progenitors can reach the bloodstream and become directly FceRI1, giving rise to another circulating MC-committed progenitor, which lacks the expression of the CD13 antigen, but might acquire it later. This latter progenitor might also reach the tissues where it differentiates terminally as described above. Red arrows represent pathways of differentiation where additional intermediary progenitors might exist, which have still not been described.
(located later in the hierarchy of the MC-restricted differentiation pathway and in the process of forming granules) than a true early hematopoietic progenitor with, among others, MC-differentiation capabilities. Based on the present report and on previously reported data, an updated scheme on the knowledge of the hierarchical process of differentiation of MCs from immature hematopoietic progenitors is proposed (see figure). An important question regarding allergic diseases is to know whether, besides being reactive to allergens, allergic patients may also have increased MC differentiation. In an attempt to provide an answer to this question, Dahlin et al have examined the frequency of their MC-committed progenitors in the PB of well-controlled asthma subjects compared with asthma patients with reduced lung function. They observed that asthma patients
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with reduced lung function had a slight but significant increase in PB MC-committed progenitors as compared with healthy individuals and also with well-controlled patients. This is of clinical significance and it is tempting to hypothesize that the quantification of these precise PB cells might serve as a marker to evaluate the severity of the disease, as well as to monitor the efficacy of antiallergic treatments. Although representing a new step forward in the knowledge of the phenotypic and biological characteristics of MC-committed progenitors in humans, this report leaves, as is the rule in biological science, still-open questions. For example, the MCs that arise from culture of their rare precursors are examined to a limited extent. Indeed, given previous data regarding the ability of MC progenitors to give rise to the full range of MC
¨ 1. Dahlin JS, Malinovschi A, Ohrvik H, et al. Lin2 CD34hi CD117int/hi FceRI1 cells in human blood constitute a rare population of mast cell progenitors. Blood. 2016;127(4):383-391. 2. Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells and inflammation. Biochim Biophys Acta. 2012;1822(1):21-33. 3. Hofmann AM, Abraham SN. New roles for mast cells in pathogen defense and allergic disease. Discov Med. 2010; 9(45):79-83. 4. Metcalfe DD, Peavy RD, Gilfillan AM. Mechanisms of mast cell signaling in anaphylaxis. J Allergy Clin Immunol. 2009;124(4):639-646. 5. Welle M. Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol. 1997;61(3):233-245. 6. Czarnetzki BM, Kruger ¨ G, Sterry W. In vitro generation of mast cell-like cells from human peripheral mononuclear phagocytes. Int Arch Allergy Appl Immunol. 1983;71(2):161-167. 7. Rottem M, Okada T, Goff JP, Metcalfe DD. Mast cells cultured from the peripheral blood of normal donors and patients with mastocytosis originate from a CD341/Fce RI2 cell population. Blood. 1994;84(8): 2489-2496. 8. Agis H, Willheim M, Sperr WR, et al. Monocytes do not make mast cells when cultured in the presence of SCF. Characterization of the circulating mast cell progenitor as a c-kit1, CD341, Ly-, CD14-, CD17-, colony-forming cell. J Immunol. 1993;151(8):4221-4227. 9. Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD341, c-kit1, and expresses aminopeptidase N (CD13). Blood. 1999;94(7):2333-2342. 10. Maaninka K, Lappalainen J, Kovanen PT. Human mast cells arise from a common circulating progenitor. J Allergy Clin Immunol. 2013;132(2):463-469. DOI 10.1182/blood-2015-12-686592 © 2016 by The American Society of Hematology
BLOOD, 28 JANUARY 2016 x VOLUME 127, NUMBER 4
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2016 127: 373-374 doi:10.1182/blood-2015-12-686592
Mast cell differentiation: still open questions? Michel Arock
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