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  • Introduction Friedenstein was the first person to describe t

    2019-06-11

    Introduction Friedenstein was the first person to describe the isolation of clonogenic, proliferating fibroblastic MSCs from rat bone marrow (BM). And they showed that colony-forming unit fibroblasts (CFU-Fs) derived stromal buy Wortmannin can serve as feeder layers for the culture of heamatopoietic stem cells (HSCs) and can differentiate into osteocytes, chondricytes and adipocytes [1,2]. Besides BM, MSCs can also be isolated from adipose tissues [3], fetal liver [4], cord blood and mobilized peripheral blood [5], fetal lung [6], placenta [7], umbilical cord [8,9], dental pulp [10], synovial membrane [11], periodontal ligament [12], endometrium [13], trabecular and compact bone [14,15] (Fig. 1). Increased evidences have shown that under appropriate culture conditions, MSCs are capable of differentiating into mesodermal, endodermal and even ectodermal cells. MSCs are capable of secreting growth factors and immunoprotective cytokines which have been used in the field of cell and organ transplantation. Most importantly, MSCs are safe, do not form teratoma, and can be used for tissue regeneration and repair [16,17]. And easy isolation, large quantity expansion and multipotential differentiation of MSCs make them ideal candidate for stem cell-based therapy and their application as gene carriers. Another intriguing feature of MSCs is that they are able to escape immune recognition and inhibit immune responses. Therefore, MSCs will be a very promising tool for immunomodulatory cell therapy in immune mediated diseases. At the time of writing, there are currently 423 clinical trials using MSCs registered at clinical-trials.gov. The clinical trials have been run for tissue repair including cardiac ischemia, limb ischemia, amyotrophic lateral sclerosis, diabetes, ischemic stroke, osteoarthritis, liver cirrhosis, and liver failure and so on. More clinical trials have been run for immune mediated diseases including GVHD, CD, MS, respiratory distress syndrome, AA, and RA (www.clinicaltrials.gov). In fact, immune mediated diseases are actually the largest kind of diseases to be clinically studied now. In addition, the biological effectiveness maybe one of important factors to determine the cell dose for infusion. The biological effectiveness always different in different tissue derived MSCs or different MSCs subpopulation. In other words, the treatment of various disease maybe will need different MSCs subpopulation and MSCs dose. And, for the same disease, MSCs dose is also variable for different tissue derived MSCs.
    Definition of MSCs Pittenger et al. firstly defined MSCs by their ability to proliferate in culture with an attached fibroblast-like morphology, by the presence of a consistent set of cell surface protein markers, and by their extensive consistent differentiation to multiple lineages mesenchymal tissue under certain controlled in vitro conditions [18]. However, to date because there is no specific or unique cell surface marker, so the definition of MSCs was always controversy. Therefore, currently MSCs have been defined by using a combination of cell surface phenotypic protein markers, plastic adherent fibroblast-like growth and functional properties. It is generally agreed that adult human MSCs express Stro-1 [19], CD105 (SH2) [20], CD73 (SH3/4) [21], CD44, CD71 (transferring receptor), CD90 (THY1), the ganglioside GD2 [22,23] and CD271 (low-affinity nerve growth factor receptor), as well as some cell adhesion molecules including intercellular adhesion molecule-1,-2 (ICAM-1,-2), integrins (α1, α2, α3, α5, α6, αV, β1, β3, β4) [24], activated leukocyte-cell adhesion molecule (ALCAM), lymphocyte function-associated antigen 3 (LFA-3), vascular cell adhesion molecule-1 (VCAM-1), and CD72 [18,25]. They also express human leukocyte antigen (HLA) class I but not class II molecules on cell surface [26,27]. Additionally, MSCs lack the expression of typical hematopoietic antigens CD11a, CD14, CD31, CD34 and CD45 [9,18], Or co-stimulatory molecules CD40, CD80, and CD86 [28,29]. The International Society for Cellular Therapy (ISCT) has offered several minimal criteria to identify MSCs which are listed as: 1) Plastic adherent fibroblast-like growth while maintaining these cells in standard conditions. 2) Expression of CD73, CD90 and CD105 markers in at least 95% of cell population and lack expression of CD34, CD45, CD14, CD11b, CD19 or CD79α and HLA-II markers as measured by flow cytometry. 3) Differentiation capability into adipogenic, osteogenic and chondrogenic lineage cells in vitro [30]. Some markers, including GD2, nestin and CD271, have been used to investigate the function of certain tissue derived MSCs or different MSCs subpopulation [22,23,31,32]. For example, GD2+ umbilical cord derived MSCs are a subpopulation of MSCs with feature of primitive precursor cells and most multipotential cells [23]. And CD106+ placenta derived MSCs are the more mature and biological functional MSCs with feature of stronger immunomodulatory capability [33] and angiogenic potential (not published).