Lymphoid-Restricted Development From Multipotent Candidate Murine Stem Cells: Distinct and Complimentary Functions of the c-kit and flt3-Ligands

• Published in: Blood Vol. 94; no. 11; pp. 3781 - 3790
• Main Authors: Borge, Ole Johan, Adolfsson, Jörgen, Jacobsen, Annica Mårtensson, Inga-Lill Mårtensson, and Sten E.W.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.12.1999; The Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; Cell Differentiation - physiology; Cell differentiation, maturation, development, hematopoiesis; Cell Lineage - physiology; Cell physiology; Cells, Cultured; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - physiology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - physiology; Lymphocytes - cytology; Membrane Proteins - physiology; Mice; Molecular and cellular biology; Proto-Oncogene Proteins c-kit - physiology; Lymphopoiesis; Enzyme; Flt3 ligand; Ligand; Transferases; Stem cell; Rodentia; Hematopoietic cell; Cell differentiation; Gene expression; Vertebrata; Mammalia; Gene; Mouse; Pluripotent cell; Hematopoiesis; Animal; Mast cell growth factor; Protein-tyrosine kinase; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.11.3781

The two tyrosine kinase receptors, c-kit and flt3, and their respective ligands KL and FL, have been demonstrated to play key and nonredundant roles in regulating the earliest events in hematopoiesis. However, their precise roles and potential interactions in promoting early lymphoid commitment and development remain unclear. Here we show that most if not all murine Lin−/loSca1+c-kit+ bone marrow (BM) cells generating B220+CD19+proB-cells in response to FL and interleukin-7 (IL-7) also have a myeloid potential. In contrast to FL + IL-7, KL + IL-7 could not promote proB-cell formation from Lin−/loSca1+c-kit+ cells. However, KL potently enhanced FL + IL-7–stimulated proB-cell formation, in part through enhanced recruitment of FL + IL-7–unresponsive Lin−/loSca1+c-kit+progenitors, and in part by enhancing the growth of proB-cells. The enhanced recruitment (4-fold) in response to KL occurred exclusively from the Lin−/loSca1+c-kit+flt3−long-term repopulating stem cell population, whereas KL had no effect on FL + IL-7–stimulated recruitment of Lin−/loSca1+c-kit+flt3+short-term repopulating cells. The progeny of FL + IL-7–stimulated Lin−/loSca1+c-kit+ cells lacked in vitro and in vivo myeloid potential, but efficiently reconstituted both B and T lymphopoiesis. In agreement with this FL, but not KL, efficiently induced expression of B220 and IL-7 receptor-α on Lin−/loSca1+c-kit+flt3+cells. Thus, whereas KL appears crucial for recruitment of FL + IL-7–unresponsive candidate (c-kit+flt3−) murine stem cells, FL is essential and sufficient for development toward lymphoid restricted progenitors from a population of (c-kit+flt3+) multipotent short-term reconstituting progenitors.