We report here that cells co-purifying with mesenchymal stem cells--termed here multipotent adult progenitor cells or MAPCs--differentiate, at the single cell level, not only into mesenchymal cells, but also cells with visceral mesoderm, neuroectoderm and endoderm characteristics in vitro. When injected into an early blastocyst, single MAPCs contribute to most, if not all, somatic cell types. On transplantation into a non-irradiated host, MAPCs engraft and differentiate to the haematopoietic lineage, in addition to the epithelium of liver, lung and gut. Engraftment in the haematopoietic system as well as the gastrointestinal tract is increased when MAPCs are transplanted in a minimally irradiated host. As MAPCs proliferate extensively without obvious senescence or loss of differentiation potential, they may be an ideal cell source for therapy of inherited or degenerative diseases.

/pdf/pluripotency-of-mesenchymal-stem-cells-derived-from-adult-200s4qlizf.pdf

Pluripotency of mesenchymal stem cells derived from adult marrow

Mesenchymal stem cells (MSCs) are multipotent cells which can give rise to mesenchymal and non-mesenchymal tissues in vitro and in vivo. Whereas in vitro properties such as (trans)differentiation capabilities are well known, there is little information regarding natural distribution and biology in the living organism. To investigate the subject further, we generated long-term cultures of cells with mesenchymal stem cell characteristics from different organs and tissues from adult mice. These populations have morphology, immunophenotype and growth properties similar to bone marrow-derived MSCs. The differentiation potential was related to the tissue of origin. The results indicate that (1) cells with mesenchymal stem characteristics can be derived and propagated in vitro from different organs and tissues (brain, spleen, liver, kidney, lung, bone marrow, muscle, thymus, pancreas); (2) MSC long-term cultures can be generated from large blood vessels such as the aorta artery and the vena cava, as well as from small vessels such as those from kidney glomeruli; (3) MSCs are not detected in peripheral blood. Taken together, these results suggest that the distribution of MSCs throughout the post-natal organism is related to their existence in a perivascular niche. These findings have implications for understanding MSC biology, and for clinical and pharmacological purposes.

/pdf/mesenchymal-stem-cells-reside-in-virtually-all-post-natal-4s1txmgth3.pdf

Mesenchymal stem cells reside in virtually all post-natal organs and tissues

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue-specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2007-0197

Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.

Background— Experimental data suggest that bone marrow–derived cells may contribute to the healing of myocardial infarction (MI). For this reason, we analyzed 10 patients who were treated by intracoronary transplantation of autologous, mononuclear bone marrow cells (BMCs) in addition to standard therapy after MI. Methods and Results— After standard therapy for acute MI, 10 patients were transplanted with autologous mononuclear BMCs via a balloon catheter placed into the infarct-related artery during balloon dilatation (percutaneous transluminal coronary angioplasty). Another 10 patients with acute MI were treated by standard therapy alone. After 3 months of follow-up, the infarct region (determined by left ventriculography) had decreased significantly within the cell therapy group (from 30±13 to 12±7%, P=0.005) and was also significantly smaller compared with the standard therapy group (P=0.04). Likewise, infarction wall movement velocity increased significantly only in the cell therapy group (from 2.0±1....

Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans

Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.

Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells

Notochordal cells interact with nucleus pulposus cells: regulation of proteoglycan synthesis.

Single human bone marrow-derived mesodermal progenitor cells (MPCs) differentiate into osteoblasts, chondrocytes, adipocytes, myocytes, and endothelial cells. To identify genes involved in the commitment of MPCs to osteoblasts we examined the expressed gene profile of undifferentiated MPCs and MPCs induced to the osteoblast lineage for 1–7 days by cDNA microarray analysis. As expected, growth factor, hormone, and signaling pathway genes known to be involved in osteogenesis were activated during differentiation. In addition, 41 transcription factors (TFs) were differentially expressed over time, including TFs with known roles in osteoblast differentiation and TFs not known to be involved in osteoblast differentiation. As the latter group of TFs coclustered with osteogenesis-specific TFs, they may play a role in osteoblast differentiation. When we compared the gene expression profile of MPCs induced to differentiate to chondroblasts and osteoblasts, significant differences in the nature and/or timing of gene activation were seen. These studies indicate that in vitro differentiation cultures in which MPCs are induced to one of multiple cell fates should be very useful for defining signals important for lineage-specific differentiation.

https://www.pnas.org/content/pnas/100/6/3305.full.pdf

Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells

Epithelial cancer of the ovary spreads by implantation of tumor cells onto the mesothelial cells lining the peritoneal cavity. The aim of this study was to identify the adhesion molecules involved in the interaction of ovarian carcinoma cells with mesothelial cells. The human ovarian carcinoma cell lines SKOV3 and NIH:OVCAR5 as well as LP9 cells, a human peritoneal mesothelial cell line, were analyzed by flow cytometry for the expression of CD44 and the β1 integrin subunit. An in vitro adhesion assay was developed whereby LP9 cells were grown as confluent monolayers, and radiolabeled ovarian carcinoma cells were monitored for their ability to adhere to the mesothelial monolayer in the presence of potential inhibitors. Each cell line was evaluated for the presence of a pericellular matrix by a particle exclusion assay. A monoclonal antibody (MAb) against the β1 integrin subunit significantly reduced the adhesion of SKOV3 cells to LP9 cells, whereas NIH:OVCAR5 adhesion to LP9 cells was significantly inhibited by a CD44 MAb. The LP9 cells produced both hyaluronic acid (a ligand for CD44) as well as several extracellular matrix molecules (ligands for the β1 integrin heterodimers). These results suggest that both CD44 and the β1 integrin heterodimers may play a role in mediating the adhesion of ovarian carcinoma cells to mesothelial cells.

/pdf/cd44-and-b1-integrin-mediate-ovarian-carcinoma-cell-adhesion-25wy5wkbz7.pdf

Dean J. Aguiar

Papers

Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells

Notochordal cells interact with nucleus pulposus cells: regulation of proteoglycan synthesis.

Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells

CD44 and β1 Integrin Mediate Ovarian Carcinoma Cell Adhesion to Peritoneal Mesothelial Cells

Erratum:Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood. 2001; 98:2615-2625