Mast cell heterogeneity – how different are they from each
other?
MC heterogeneity was first described in the mid-60s by differences in
histochemical staining features, and the concept of connective tissue
mast cells (CTMCs) and mucosal mast cells (MMCs) was born55,56. In humans, different MC subpopulations have
been defined by their protease content; those that express tryptase
(MCT), tryptase and chymase (MCTC) and
chymase only (MCC) 57,58. The latter
was, for a long time, controversial, and the presence of chymase-only
positive MCs has remained ignored and virtually unstudied. The two
distinct MC subpopulations, MCT and
MCTC, as well as the MMC and CTMC, differ in their
localization, mediator content and responsiveness to secretagogues59.
Besides dividing MCs into subpopulations based on their localization or
protease content, there are also definitions of MCs being either
constitutive or inducible, pro- or anti-inflammatory, or pro- or
anti-tumorigenic (MC1 or MC2) 24,60,61. While the
division into constitutive and inducible subpopulations might be related
to the prenatal origin of the MC (see above), the latter is probably
dependent on changes in the microenvironment during an inflammation. It
is clear that MCs in different organs differ in their receptor and
mediator expression, but also within a single tissue there is a
considerable heterogeneity, e.g., among human lung MCT62. Furthermore, the gene/protein expression within
this MCT subpopulation changes during inflammatory
responses 63. A question to address is if these
changes relate to different subtypes or a plasticity within the MC
population.
The origin and development of different MC subpopulations have been
enigmatic, but one clue was described recently as mentioned above33. For hematopoiesis in the adult, the question has
been if there are several different MC progenitor populations in
circulation, or if there is one progenitor population that has the
capacity to differentiate and mature into any of the MC subtypes. In
other words, is the heterogeneity driven by locally produced factors or
is it driven by the recruitment of different types of designated
progenitors? In a study where this question was addressed, the results
suggested the existence of a common MC progenitor that gives rise to all
MC subpopulations 64. However, single cell RNA
sequencing and single cell cultures will likely provide further proof
and insights into this process.
The separation of MCs into different subpopulations based on their
protease content or histochemical properties is rather simplistic. MCs
show a great plasticity, and detailed analysis of protease expression in
human lung MCs demonstrate a gradient in the expression of the different
proteases in these cells 65. Transcriptome comparisons
of MCs from different mouse tissues with other immune cells revealed
that MCs form a distinct population well separated from all other immune
cells 66. Within the MC population there was a
substantial heterogeneity across tissues 66.
Similarly, proteome analysis of human skin and fat MCs confirmed the
unique identity of MCs among immune lineages, including the granulocytes
(neutrophils, eosinophils and basophils) 67. It will
be interesting, when single MC RNA sequencing data from human tissues
are available, to further decipher MC heterogeneity and plasticity. This
will give further insight into MC heterogeneity and might provide a
clearer view about differences among MCs within the same tissue.