Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body

Abstract

The transplantation of primitive human cells into sublethally irradiated immunedeficient mice is the well-established in vivo system for the investigation of human hematopoietic stem cell function. Although mast cells are the progeny of hematopoietic stem cells, human mast cell development in mice that underwent human hematopoietic stem cell transplantation has not been reported. Here we report on human mast cell development after xenotransplantation of human hematopoietic stem cells into nonobese diabetic severe combined immunodeficient (NOD/SCID)/␥ c null (NOG) mice with severe combined immunodeficiency and interleukin 2 (IL-2) receptor ␥-chain allelic mutation. Supported by the murine environment, human mast cell clusters developed in mouse dermis, but they required more time than other forms of human cell reconstitution. In lung and gastric tract, mucosal-type mast cells containing tryptase but lacking chymase located on gastric mucosa and in alveoli, whereas connective tissue-type mast cells containing both tryptase and chymase located on gastric submucosa and around major airways, as in the human body. Mast cell development was also observed in lymph nodes, spleen, and peritoneal cavity but not in the peripheral blood. Xenotransplantation of human hematopoietic stem cells into NOG mice can be expected to result IntroductionMast cells are recognized as the principal cells which initiate immunoglobulin E (IgE)-dependent immediate hypersensitivity and also as the cells which contribute to innate immunity and tissue remodeling. 1,2 There are 2 phenotypically distinct mast cell subpopulations in rodents: connective tissue-type mast cells (CTMCs) and mucosal-type mast cells (MMCs). These populations differ in location, cell size, staining characteristics, ultrastructure, mediator content, and T-cell dependency. 3 Proliferation of rodent MMCs is dependent on T-cell-derived cytokines, 3,4 whereas that of CTMCs is supported by stem cell factor (SCF). In humans, mast cells are distinguished on the basis of their protease composition, 5,6 MC TC contains tryptase and chymase in its granules and is predominant in skin and intestinal submucosa, like CTMCs in rodents. MC T also contains tryptase, but lacks chymase, and is predominant in the alveolar wall and gastric mucosa, similar to MMCs in rodents. Human mast cells were reported to develop only under the influence of SCF, but T-cell-derived interleukin 3 (IL-3) has little affect on their differentiation. 7 Recently, human intestinal mast cells were reported to respond to IL-3 by enhancing their growth, 8 but SCF is still an indispensable factor for human mast cells. Mast cells are the progenies of hematopoietic stem cells (HSCs). 9,10 In mice, the progenitor cells capable of becoming mast cells leave the bone marrow and enter the circulation but complete their differentiation into mast cells only after arriving in peripheral tissues such as lung, bowel, and skin. 10,11 Unfortunately, the developmental mechanism of human mast cells remains far less clear, possibly bec...

Activation of peroxisome proliferator‐activated receptor gamma suppresses mast cell maturation involved in allergic diseases

“…To confirm this inhibition of differentiation, we performed alcian blue-safranin staining, which shows a specific red color in mature CTMCs and a blue color in MMC-like immature mast cells (1)(2)(3)(4)(5). Vehicle-treated bone marrow-progenitors almost totally differentiated into CTMCs by 7-8 weeks by this measure (Figs 4I and J, approximately 80%).…”

“…To distinguish MMC-like immature mast cells and CTMCs, alcian blue-safranin staining was performed. CTMCs were stained with a red and MMC-like immature mast cells were stained with a light blue color (1)(2)(3)(4)(5).…”

“…All animal experiments were approved by the institutional animal care and use committee of Osaka University and Yokohama City University School of Medicine. Bone marrow-derived mast cells were collected from the femur and tibia and differentiated according to the methods previously (1)(2)(3)(4)(5). After 4 weeks, stem cell factor (SCF, 50 ng/ml) was added in culture medium.…”

“…In mammals, there are two distinct mast cell subpopulations, connective tissue-type (CTMCs) and mucosal-type mast cells (MMCs) (1)(2)(3)(4)(5). These cell types differ in location, staining characteristics, protease expression pattern, and histamine content.…”

“…Keywords allergic disease; differentiation; dermatitis; mast cell; peroxisome proliferator-activated receptor gamma Mast cells are considered to play an important role in many allergic diseases and inflammatory responses (1)(2)(3)(4)(5). In mammals, there are two distinct mast cell subpopulations, connective tissue-type (CTMCs) and mucosal-type mast cells (MMCs) (1)(2)(3)(4)(5).…”