Identification of Lin(-)Sca1(+)kit(+)CD34(+)Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients.
In clinical bone marrow transplantation, the severe cytopenias induced by bone marrow ablation translate into high risks of developing fatal infections and bleedings, until transplanted hematopoietic stem and progenitor cells have replaced sufficient myeloerythroid offspring. Although adult long-term hematopoietic stem cells (LT-HSCs) are absolutely required and at the single-cell level sufficient for sustained reconstitution of all blood cell lineages, they have been suggested to be less efficient at rapidly reconstituting the hematopoietic system and rescuing myeloablated recipients. Such a function has been proposed to rather be mediated by less well-defined short-term hematopoietic stem cells (ST-HSCs). Herein, we demonstrate that Lin(-)Sca1(+)kit(hi)CD34+ short-term reconstituting cells contain 2 phenotypically and functionally distinct subpopulations: Lin(-)Sca1(+)kit(hi)CD34(+)flt3- cells fulfilling all criteria of ST-HSCs, capable of rapidly reconstituting myelopoiesis, rescuing myeloablated mice, and generating Lin(-)Sca1(+)kit(hi)CD34(+)flt3+ cells, responsible primarily for rapid lymphoid reconstitution. Representing the first commitment steps from Lin(-)Sca1(+)kit(hi) CD34(-)flt3- LT-HSCs, their identification will greatly facilitate delineation of regulatory pathways controlling HSC fate decisions and identification of human ST-HSCs responsible for rapid reconstitution following HSC transplantations.
Yang
Liping
L
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, BMC B10, Klinikgatan 26, 221 84 Lund, Sweden.
Bryder
David
D
Adolfsson
Jörgen
J
Nygren
Jens
J
Månsson
Robert
R
Sigvardsson
Mikael
M
Jacobsen
Sten Eirik W
SE
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D000950:Antigens, Ly / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018189:Immunomagnetic Separation; D016130:Immunophenotyping; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014916:Whole-Body Irradiation; D051941:fms-Like Tyrosine Kinase 3
D018952:Antigens, CD34; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D011518:Proto-Oncogene Proteins; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3