Delineation of T-progenitor cell activity within the CD34+ compartment of adult bone marrow.
T-cell production is largely dependent on the presence of a thymus gland where CD34+ precursors mature into T lymphocytes. Prethymic stages of T-cell development are less defined. Therefore, this study aims to delineate T-progenitor cell potential within the CD34+ Lineage--(Lin-) cell compartment of adult bone marrow (ABM). Fractionation of CD34+ Lin- ABM cells with CD45RA, Thy-1, CD38, and HLA-DR failed to absolutely segregate T-cell reconstituting ability, indicating broad distribution of T-progenitor cell potential. Titration experiments showed that low numbers of CD34+ Lin- CD45RA+ (RA+) cells had greater thymus repopulating ability than CD34+ Lin- CD45RA- cells (RA-). The great majority (> 95%) of RA+ cells expressed CD38, HLA-DR and 70% to 90% of RA+ cells lacked Thy-1 surface expression. RA+ cells contained colony-forming unit granulocyte-macrophage (CFU-GM) progenitor cells but were depleted of erythroid potential, did not provide hematopoietic reconstitution of human bone fragments implanted into SCID mice, and did not efficiently maintain CD34+ cells with secondary clonogenic potential in bone marrow cultures. Thus, RA+ cells are oligopotent (nonprimitive) CD34+ progenitors with T-cell reconstituting ability. In contrast, these same assays indicated that CD34+ Lin- CD45RA- cells (RA- cells) comprised hematopoietic stem cells (HSC) with primitive multilineage (T, B, myeloid, and erythroid) hematopoietic potential. It was confirmed that HSC-containing populations, such as CD34+ Lin- CD45RA- Thy-1+ cells had thymus repopulating ability. Culture of RA- cells on murine bone marrow stromal cells in the presence of interleukin (IL)-3, IL-6, and leukemia inhibitory factor (LIF) generated CD34+ CD45RA+ progeny engrafting in a secondary severe combined immunodeficiency (SCID)-hu thymus assay. Altogether, our results underscore the fact that T-cell reconstituting potential can be dissociated from HSC activity. Furthermore, we speculate that HSC might develop into the T lineage indirectly, via differentiation into an intermediate oligopotent CD34+ CD45RA+ stage. Finally, T-progenitor cells can be cultured in vitro.
Galy
A H
AH
Experimental Cellular Therapy Group, Systemix Inc, Palo Alto, CA 94304, USA.
Cen
D
D
Travis
M
M
Chen
S
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Chen
B P
BP
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism*; D018952:Antigens, CD34; D000943:Antigens, Differentiation / Q000378:metabolism; D001854:Bone Marrow Cells; D006684:HLA-DR Antigens / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000166:cytology*; D008562:Membrane Glycoproteins; D013601:T-Lymphocytes / Q000166:cytology*; D018800:Thy-1 Antigens / Q000378:metabolism
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; D018800:Thy-1 Antigens; D017493:Leukocyte Common Antigens; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1