Mesenchymal Stem Cells Proteins


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 Mesenchymal Stem Cells Proteins Background

In 1976 Friedenstein and colleagues isolated a group of non-hematopoietic colony-forming progenitor cells from mouse BM that showed further plastic-adherence and fibroblast-like morphology. Since then extensive studies have been conducted to further characterize this cell population accompanied by a constant refining of their nomenclature from “colony forming unit fibroblasts and osteogenic stem cells” over “multipotent mesenchymal stromal cells” (International Society for Cellular Therapy, 2006) to the most recent proposed term “medicinal signaling cells”. These different categories arose to highlight certain cell characteristics elucidated during in vitro analyses like their potential to differentiate into multiple mesenchymal cell types such as osteocytes, adipocytes and chondrocytes, or the ability to secrete bioactive compounds and regulate the local immune response. But the most prevalent term to describe these original BM-derived cells remains “mesenchymal stem cells” (MSCs) introduced by Caplan in 1991 based on their sternness properties. In order to be defined as a stem cell, a cell has to meet the following criteria: capacity of self-renewal and ability to differentiate into one or more functionally mature specialized cells.
Beyond this controversy about their nomenclature, researchers have been able to isolate MSCs from other species such as humans and from many other tissue types. Apart from BM, MSCs were shown to reside within distinctive adult tissues-for example, adipose tissue, peripheral blood, muscle and neonatal tissues-for example, umbilical cord blood, placenta and amniotic fluid. The reported studies show, however, inconsistencies in the applied methodologies to isolate and expand MSCs. 
At the forefront of this issue is the absence of a MSC-specific marker that could be used to definitely isolate and characterize MSCs. The routinely used method to collect MSCs exploiting their plastic adherence often yields a heterogeneous population of MSCs, where the culture is contaminated with undesired cell types like hematopoietic cells in BM-derived MSC cultures. Furthermore, the isolated MSC population demonstrates heterogeneity itself with respect to proliferation rate, differentiation capacity and gene expression profile dependent on the tissue of origin and isolation method. 
To increase the transparency among investigations and reduce experimental variations, the International Society for Cellular Therapy (ISCT) proposed three minimal criteria for defining human MSCs in 2006. These include traditional MSC characteristics like their adherence to plastic and in vitro multipotent differentiation potential, as well as positive and negative surface markers, namely cluster of differentiation (CD) markers. The CD markers were selected primarily to distinguish between MSCs and hematopoietic cells. Thus, positive markers for MSCs (CD73, CD90, CD 105) are absent from most hematopoietic cells, while negative markers for MSCs (CD34, CD45, CD 11b, CD14, CD79 alpha, CD19, HLA Class II) are expressed by hematopoietic cells. 
The identification of MSCs, based on the expression profile of specific CD markers, is not robust due to the phenotypic plasticity of MSCs observed during in vitro cultivation. Moreover, the current recommended ISCT criteria for human MSCs cannot be translated directly to animal models. For instance, BM-derived MSCs isolated from dog, sheep and goat demonstrated no cross-reaction with anti-human monoclonal CD73 and CD90 antibodies, important positive MSC markers in humans. The potential lack of CD73 and CD90 expression by MSCs from other species has to be further confirmed using species-specific antibodies, as CDs might not be evolutionarily conserved across species leading to false negative results. On top of that, Peister et al. manifested in 2004 that MSC surface marker expression profile could vary between mouse strains and thus intra-species.
Considerable effort has been devoted to identify a MSC-specific surface or genetic marker to balance the current characterization discrepancy between MSCs and their BM co-resident, the hematopoietic stem cells (HSC). It has been thought for decades that both adult, multipotent stem cell types, MSC and HSC, derive from the mesoderm and would give rise to mesenchymal or hematopoietic cell lines respectively. New studies have reported the ability of MSCs to transdifferentiate into cells of endodermal, e.g. lung cells and ectodermal, e.g. neurons. This has raised a debate about the exclusively mesodermal origin of MSCs.
In the past years, MSCs have attracted much interest as an adult stem cell type with self-renewal capacity and trilineage differentiation potential into adipocytes, chondrocytes, and osteocytes. Their in vivo identity, normal physiological function, and original niche are under intense investigation moving the research field forward to advance potential applications of MSCs.

Applications of Mesenchymal Stem Cells
The discovery of adult stem cells that are found lifelong throughout the body dividing to replenish dying cells and regenerate damaged tissues has revolutionized the therapeutic and regenerative medicine field. In contrast to embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), adult stem cells including MSCs show restricted proliferation and lineage differentiation. However, adult stem cells circumvent two significant limitations of ESC and iPSC: ethical and legal issues associated with the destruction of the embryo to isolate ESCs from the inner cell mass of the blastocyst and the potential to form teratomas. Therefore, the possible therapeutic use of MSCs has been under pre-clinical investigation for many years and revealed various beneficial effects encouraging MSC-mediated therapies. 
The first clinical trial using culture-expanded autologous MSCs was carried out in 1995 to treat 15 patients suffering from hematological malignancies in remission. No treatment-associated adverse effects were reported and data showed support of HSC transplantation. Since then MSCs have made their way into multiple clinical trials with 593 studies currently listed on the international registry www.clinicaltrials.gov (last updated: 23/02/2016). In general the applications of MSCs can be attributed to four biological characteristics: 1) multipotent differentiation potential, 2) capacity to migrate and engraft, 3) immunomodulation, and 4) production of trophic factors. These characteristics contribute to the therapeutic effects of MSCs and therefore, it is not surprising that the potential applications of MSCs range from tissue engineering to immune disorder therapy of multiple sclerosis and graft-versus-host disease.

Mesenchymal Stem Cells reference
1. Friedenstein A J, Gorskaja J F, Kulagina N N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs[J]. Experimental hematology, 1976, 4(5): 267-274.
2. Nombela-Arrieta C, Ritz J, Silberstein L E. The elusive nature and function of mesenchymal stem cells[J]. Nature Reviews Molecular Cell Biology, 2011, 12(2): 126-131.
3. Popov B V, Serikov V B, Petrov N S, et al. Lung epithelial cells induce endodermal differentiation in mouse mesenchymal bone marrow stem cells by paracrine mechanism[J]. Tissue engineering, 2007, 13(10): 2441-2450.
4. Lazarus H M, Haynesworth S E, Gerson S L, et al. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use[J]. Bone marrow transplantation, 1995, 16(4): 557-564.