Mast cell differentiation: still open questions?

In this issue of Blood, Dahlin et al report on a minor circulating human mast cell (MC) progenitor cell population (lineage-negative [Lin⁻]/CD34^hi/CD117^int/hi/high-affinity immunoglobulin E receptor-positive [FcεRI⁺]), 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 

MCs 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 (MC_T), mostly found in mucosal tissues, and MCs containing tryptase, chymase, and carboxypeptidase A (MC_TC), 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) CD34⁺/FcεRI⁻ progenitors which transiently circulate in the bloodstream as morphologically undifferentiated cells⁷  and that these cells, which are composed of a subset of circulating CD34⁺/CD117⁺/Ly⁻/CD14⁻/CD17⁻ 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 CD34⁺/CD117⁺/CD13⁺/FcεRI⁻ 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 PB-derived cell populations giving rise only to CD117⁺/FcεRI⁺ 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 Lin⁻/CD34^hi/CD117^int/hi/FcεRI⁺ cell subset, expressing or not expressing CD13, gave rise to CD117⁺/FcεRI⁺ granulated tryptase-positive MCs at a high frequency (>70%). This frequency was far lower when the authors attempted to work with the FcεRI⁻ cell subsets (the frequency of Lin⁻/CD34^hi/CD117^int/hi/FcεRI⁻ cells giving rise to CD117⁺/FcεRI⁺ tryptase-positive MCs is between 2.7% and 5.7%), meaning that acquiring the expression of FcεRI by CD34⁺/CD117⁺ cells commits them definitively to the MC lineage. Subsequently, the authors performed different maneuvers to further enrich the Lin⁻/CD34^hi/CD117^int/hi/FcεRI⁺ cell subset into even more MC-committed elements, by using exclusion of CD45RA⁺ cells and by further purification of cells expressing or not expressing CRTH2 (a PGD2 receptor) and/or integrin β7. 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 Lin⁻/CD34^hi/CD117^int/hi/FcεRI⁺ or Lin⁻/CD34^hi/CD117^int/hi/FcεRI⁺/CD45RA⁻/CRTH2⁻/integrin β7⁺ cells have very low dividing capabilities, which was somewhat expected from a MC-committed progenitor already expressing FcεRI 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” (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 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 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.