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.