Studies on hematopoiesis have focused on the function and composition of human bone marrow stroma. Stroma function gives hematopoietic stem cells the microenvironment appropriate for self-renewal and/or prompt differentiation into hematopoietic progenitor cells, then into terminal specialized cells. Human bone marrow stroma has been dissected into hematopoietic and nonhematopoietic components. The former includes hematopoietic-derived cells, mainly macrophages, while the latter, still poorly characterized, is composed mainly of endothelial and mesenchymal stem cells and their derivatives (adipocytes, chondrocytes, cells of the osteogenic lineage). Isolation of bone marrow mesenchymal stem cells has made available a population of adherent cells, belonging to the non-hematopoietic stroma, which are morphologically and phenotypically homogeneous. This review will focus on: (i) definition of bone marrow stroma and mesenchymal stem cells; (ii) methods of mesenchymal stem cell isolation, morphological and phenotypic characterization; (iii) mesenchymal stem cell functional and differentiation properties and (iv) therapeutic applications of mesenchymal stem cells.

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The TAL-1 gene specifies a basic helix-loop-helix domain (bHLH) transcription factor, which heterodimerizes with E2A gene family proteins. tal-1 protein is abnormally expressed in the majority of T-cell acute lymphoblastic leukemias (T-ALLs). tal-1 is expressed and plays a significant role in normal erythropoietic differentiation and maturation, while its expression in early myeloid differentiation is abruptly shut off at the level of late progenitors/early differentiated precursors (G. The tal-1 protein, while absent in normal adult T lymphocytes (5), is constitutively expressed in Ͼ60% of T-cell acute lymphoblastic leukemias (T-ALLs), due to the (1;14)(p32;q11) translocation (5,8,18), specific interstitial deletions of the 5Ј noncoding gene region (tal d ) (6), or unidentified alterations (4).LIn the homologous-recombination mouse model, lack of tal-1 determines midgestation embryonic lethality due to the absence of primitive hematopoiesis (44, 48). Furthermore, in vivo and in vitro studies of tal-1 Ϫ/Ϫ embryonic stem cells indicate a crucial role for tal-1 in the generation of all definitive lineages (40,43). In early development tal-1 is also expressed in nervous system, smooth muscle, and endothelial cells (21,29).In adult cells, tal-1 is expressed in normal erythroblasts, megakaryocytes, and mast cells (36, 41), as well as in erythroleukemic, megakaryocytic, and mast cell lines (21, 56). In human hematopoiesis, tal-1 is expressed in hematopoietic progenitor cell (HPC) differentiation/maturation through the erythroid and megakaryocytic lineages (13,36,41,53). Interestingly, tal-1 is also expressed in the early stages of HPC differentiation along the granulopoietic or monopoietic pathways; in both cases, however, the expression is abruptly shut off at the level of late HPC/early differentiated precursors (13). Functional studies with antisense oligodeoxynucleotides targeting tal-1 mRNA indicate a functional role for tal-1 in erythropoiesis, particularly at the advanced HPC differentiation stage, but not in granulo-and monocytopoiesis (13); the functional role in erythropoiesis is further indicated by studies on enforced tal-1 expression in the K562 erythroleukemic line (1,20) and differentiating erythroid HPCs (54a).The tal-1/E2A heterodimer recognizes a subset of E-box responsive elements (27,28). However, tal-1/E2A target genes have not yet been identified. In erythroblasts, formation of the tal-1/E2A complex is inhibited by the HLH Id2 protein, which competes with tal-1 for E2A protein binding (13). Furthermore, tal-1 is associated in complex with Lmo2/rbtn-2 protein in erythroid (54; also, unpublished data) and T leukemic (58) cells.While the function of tal-1 in normal hematopoiesis has been extensively investigated, the effects of aberrant tal-1 expression are under scrutiny (see Discussion). We have investigated the action of ectopic tal-1 on cell proliferation/differentiation and the underlying mechanisms. The selected cell models include phenotypically normal and leukemic myeloid precursors, frozen ...