Institute of Biological Medicine, Moscow The formation of the concept of a mesenchymal stem cell (MSC) is a priority of Russian biological science. A. Ya. Fridenshtein and his colleagues were the first who experimentally proved the existence of MSC. Osteogenic potential of fibroblastlike bone marrow cells of different mammalian species was demonstrated [25,26]. Fibroblast-like bone marrow cells often formed discrete adhesive colonies in vitro [27,28,47]. After heteroand orthotopic transplantation in vivo cloned cells from these colonies formed bone, cartilaginous, fibrous, and adipose tissues [48]. Intensive self-renewal and multipotency of fibroblast-like colony-forming cells from the bone marrow allowed Fridenshtein and Owen to formulate a concept of multipotent mesenchymal precursor cells (MPC) [62]. An ordered chain of finely regulated cell proliferation, migration, differentiation, and maturation processes underlies the formation of the majority of cell lineages in adult organisms. The earliest cell elements in this chain are stem cells (SC). Along with extensive self-renewal capacity, SC possess a great differentiation potential. Apart from well studied hemopoietic and intestinal SC, other SC classes were recently discovered in adult organism. Until recently it was considered that SC in adults can give rise to cell lines specific to tissues where these cells are located; however, new facts necessitated revision of this concept. Hemopoietic SC capable of differentiating into all cell elements of the blood, can also be a source of hepatic oval cells [65]; neural SC, precursors of neurons and glia [2,3], serve as the source of early and committed hemopoietic precursors [10]. MSC, a source of bone, cartilaginous, and adipose tissue cells, can differentiate into neural cells [46]. Tissue growth and reparation are associated with migration of uncommitted precursor cells from other tissues. During muscle tissue reparation mesenchymal SC migrate from the bone marrow into skeletal muscles [24]. Hence, in addition to capacity to unlimited division and reproduction of a wide spectrum of descendants of a certain differentiation line, adult SC are characterized by high plasticity. The existence of a rare type of somatic pluripotent SC, common precursors of all SC in an adult organism, is hypothesized [79]. Another important characteristic of SC is their migration from the tissue niche into circulation, which was experimentally proven for hemopoietic and MSC [69,73]. For activation of the differentiation program, circulating SC should get into an appropriate microenvironment [75,78]. A potent stimulus for investigation of SC is the possibility of their clinical use in cell and gene therapy. The bone marrow contains multipotent MSC, which can be easily isolated and cultured in vitro. It is therefore interesting to analyze some fundamental aspects of MSC biology and the possibilities of their clinical use. MSC descendants are involved in the formation of bones, cartilages, tendons, adipose and muscle tissues, and stroma maintaining the hemopoiesis [12,19,51]. The term MPC is used to denote MSC and their committed descendants capable of differentiating into at least two types of mature cells, which are present in the bone marrow and some mesenchymal tissues [16,19,57,82].

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) represent a promising tool for new clinical concepts in supporting cellular therapy. Bone marrow (BM) was the first source reported to contain MSCs. However, for clinical use, BM may be detrimental due to the highly invasive donation procedure and the decline in MSC number and differentiation potential with increasing age. More recently, umbilical cord blood (UCB), attainable by a less invasive method, was introduced as an alternative source for MSCs. Another promising source is adipose tissue (AT). We compared MSCs derived from these sources regarding morphology, the success rate of isolating MSCs, colony frequency, expansion potential, multiple differentiation capacity, and immune phenotype. No significant differences concerning the morphology and immune phenotype of the MSCs derived from these sources were obvious. Differences could be observed concerning the success rate of isolating MSCs, which was 100% for BM and AT, but only 63% for UCB. The colony frequency was lowest in UCB, whereas it was highest in AT. However, UCB-MSCs could be cultured longest and showed the highest proliferation capacity, whereas BM-MSCs possessed the shortest culture period and the lowest proliferation capacity. Most strikingly, UCB-MSCs showed no adipogenic differentiation capacity, in contrast to BM- and AT-MSCs. Both UCB and AT are attractive alternatives to BM in isolating MSC: AT as it contains MSCs at the highest frequency and UCB as it seems to be expandable to higher numbers.

Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue.

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.

Mesenchymal stem cells or multipotent stromal cells (MSCs) isolated from the bone marrow of adult organisms were initially characterized as plastic adherent, fibroblastoid cells with the capacity to generate heterotopic osseous tissue when transplanted in vivo. In recent years, MSCs or MSC-like cells have been shown to reside within the connective tissue of most organs, and their surface phenotype has been well described. A large number of reports have also indicated that the cells possess the capacity to transdifferentiate into epithelial cells and lineages derived from the neuroectoderm. The broad developmental plasticity of MSCs was originally thought to contribute to their demonstrated efficacy in a wide variety of experimental animal models of disease as well as in human clinical trials. However, new findings suggest that the ability of MSCs to alter the tissue microenvironment via secretion of soluble factors may contribute more significantly than their capacity for transdifferentiation in tissue repair. Herein, we critically evaluate the literature describing the plasticity of MSCs and offer insight into how the molecular and functional heterogeneity of this cell population, which reflects the complexity of marrow stroma as an organ system, may confound interpretation of their transdifferentiation potential. Additionally, we argue that this heterogeneity also provides a basis for the broad therapeutic efficacy of MSCs.

Disclosure of potential conflicts of interest is found at the end of this article.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2007-0637

Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views.

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

Haemopoiesis is sustained by two main cellular components, the haematopoietic cells (HSCs) and the mesenchymal progenitor cells (MPCs). MPCs are multipotent and are the precursors for marrow stroma, bone, cartilage, muscle and connective tissues. Although the presence of HSCs in umbilical cord blood (UCB) is well known, that of MPCs has been not fully evaluated. In this study, we examined the ability of UCB harvests to generate in culture cells with characteristics of MPCs. Results showed that UCB-derived mononuclear cells, when set in culture, gave rise to adherent cells, which exhibited either an osteoclast- or a mesenchymal-like phenotype. Cells with the osteoclast phenotype were multinucleated, expressed TRAP activity and antigens CD45 and CD51/CD61. In turn, cells with the mesenchymal phenotype displayed a fibroblast-like morphology and expressed several MPC-related antigens (SH2, SH3, SH4, ASMA, MAB 1470, CD13, CD29 and CD49e). Our results suggest that preterm, as compared with term, cord blood is richer in mesenchymal progenitors, similar to haematopoietic progenitors.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2000.01986.x

Mesenchymal progenitor cells in human umbilical cord blood.

Within the bone marrow stroma there exists a subset of nonhematopoietic cells referred to as mesenchymal stem or mesenchymal progenitor cells. These cells can be ex vivo expanded and induced, either in vitro or in vivo, to terminally differentiate into osteoblasts, chondrocytes, adipocytes, tenocytes, myotubes, neural cells, and hematopoietic-supporting stroma. The multipotential of these cells, their easy isolation and culture, as well as their high ex vivo expansive potential make these cells an attractive therapeutic tool. In this work we will review the information dealing with the biology of mesenchymal progenitors as it has been revealed mainly by ex vivo studies performed with bone marrow-derived cells. The discussed topics include, among others, characteristics of mesenchymal progenitors, evidence for the existence of a vast repertoire of uncommitted and committed progenitors both in the bone marrow and in mesenchymal tissues, a diagram for their proliferative hierarchy, and comments on mobilization, microenvironment, and clinical use of mesenchymal progenitors. Despite the enormous data available at molecular and cellular levels, it is evident that a number of fundamental questions still need to be resolved before mesenchymal progenitors can be used for safe and effective clinical applications in the context of both cell and gene therapies.

Mesenchymal stem cells

Human Cord Blood-Derived Mesenchymal Stem Cells Home and Survive in the Marrow of Immunodeficient Mice after Systemic Infusion:

Within the complex cellular arrangement found in the bone marrow stroma there exists a subset of nonhematopoietic cells referred to as mesenchymal progenitor cells (MPC). These cells can be expanded ex vivo and induced, either in vitro or in vivo, to terminally differentiate into at least seven types of cells: osteocytes, chondrocytes, adipocytes, tenocytes, myotubes, astrocytes and hematopoietic-supporting stroma. This broad multipotentiality, the feasibility to obtain MPC from bone marrow, cord and peripheral blood and their transplantability support the impact that the use of MPC will have in clinical settings. However, a number of fundamental questions about the cellular and molecular biology of MPC still need to be resolved before these cells can be used for safe and effective cell and gene therapies intended to replace, repair or enhance the physiological function of the mesenchymal and/or hematopoietic systems.

/pdf/biology-and-clinical-utilization-of-mesenchymal-progenitor-2y0odutrim.pdf

Biology and clinical utilization of mesenchymal progenitor cells.

gp130 Activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells

Alejandro Erices

Papers

Mesenchymal progenitor cells in human umbilical cord blood.

Mesenchymal stem cells

Human Cord Blood-Derived Mesenchymal Stem Cells Home and Survive in the Marrow of Immunodeficient Mice after Systemic Infusion:

Biology and clinical utilization of mesenchymal progenitor cells.

gp130 Activation by soluble interleukin-6 receptor/interleukin-6 enhances osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells