Cathepsin K maintains the compartment of bone marrow T lymphocytes in vivo

• Published in: Immunity, Inflammation and Disease Inflammation and Disease, 2021-06, Vol.9 (2), p.521-532
• Main Authors: Hausinger, Renate, Hackl, Marianne, Jardon Alvarez, Ana, Kehr, Miriam, Romero Marquez, Sandra, Hettler, Franziska, Kehr, Christian, Grziwok, Sandra, Schreck, Christina, Peschel, Christian, Istvánffy, Rouzanna, Oostendorp, Robert A. J.
• Format: Article
• Language: English
• Subjects: Antibodies; Bone marrow; cathepsin; cathepsin K; Cell cycle; CTSK; Experiments; Flow cytometry; hematopoietic stem cells; Laboratory animals; lymphopoiesis; marrow; microenvironment; niche; Original Research; Osteoporosis; stem cells; Thymus gland
• ISSN: 2050-4527; 2050-4527
• DOI: 10.1002/iid3.412

In this study, we investigated the influence of the loss of cathepsin K (Ctsk) gene on the hematopoietic system in vitro and in vivo. We found that cultures with lineage− SCA1+ KIT+ (LSK) cells on Ctsk deficient stromal cells display reduced colony formation and proliferation, with increased differentiation, giving rise to repopulating cells with reduced ability to repopulate the donor LSKs and T cell compartments in the bone marrow (BM). Subsequent in vivo experiments showed impairment of lymphocyte numbers, but, gross effects on early hematopoiesis or myelopoiesis were not found. Most consistently in in vivo experimental settings, we found a significant reduction of (donor) T cell numbers in the BM. Lymphocyte deregulation is also found in transplantation experiments, which revealed that Ctsk is required for optimal regeneration of small populations of T cells, particularly in the BM, but also of thymic B cells. Interestingly, cell nonautonomous Ctsk regulates both B and T cell numbers, but T cell numbers in the BM require an additional autonomous Ctsk‐dependent process. Thus, we show that Ctsk is required for the maintenance of hematopoietic stem cells in vitro, but in vivo, Ctsk deficiency most strongly affects lymphocyte homeostasis, particularly of T cells in the BM. This manuscript describes how stromal cathepsin K regulates stem cells in vitro and in vivo. Transplantation experiments show that the main effect of the loss of the cathepsin K gene in vivo is a deregulated lymphocyte homeostasis, particularly the T lymphocyte subsets in the bone marrow compartment, in both autonomous and nonautonomous manners.