Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow

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Abstract
Human mesenchymal stem/progenitor cells (MSCs) have been identified in adult bone marrow, but little is known about their presence during fetal life. MSCs were isolated and characterized in first-trimester fetal blood, liver, and bone marrow. When 106 fetal blood nucleated cells (median gestational age, 10+2 weeks [10 weeks, 2 days]) were cultured in 10% fetal bovine serum, the mean number (± SEM) of adherent fibroblastlike colonies was 8.2 ± 0.6/106 nucleated cells (69.6 ± 10/μL fetal blood). Frequency declined with advancing gestation. Fetal blood MSCs could be expanded for at least 20 passages with a mean cumulative population doubling of 50.3 ± 4.5. In their undifferentiated state, fetal blood MSCs were CD29+, CD44+, SH2+, SH3+, and SH4+; produced prolyl-4-hydroxylase, α-smooth muscle actin, fibronectin, laminin, and vimentin; and were CD45−, CD34−, CD14−, CD68−, vWF−, and HLA-DR−. Fetal blood MSCs cultured in adipogenic, osteogenic, or chondrogenic media differentiated, respectively, into adipocytes, osteocytes, and chondrocytes. Fetal blood MSCs supported the proliferation and differentiation of cord blood CD34+cells in long-term culture. MSCs were also detected in first-trimester fetal liver (11.3 ± 2.0/106 nucleated cells) and bone marrow (12.6 ± 3.6/106 nucleated cells). Their morphology, growth kinetics, and immunophenotype were comparable to those of fetal blood-derived MSCs and similarly differentiated along adipogenic, osteogenic, and chondrogenic lineages, even after sorting and expansion of a single mesenchymal cell. MSCs similar to those derived from adult bone marrow, fetal liver, and fetal bone marrow circulate in first-trimester human blood and may provide novel targets for in utero cellular and gene therapy.