Isolation and identification of MSCs

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

Part II. Cancer stem cells

MSCs are multipotent progenitor cells, first discovered in bone marrow by Friedenstein et al. (1970). Since they possess the capacity to self-renew and differentiate, they are considered stem cells (Caplan, 1991). They reside primarily in the bone marrow but are also found in a variety of other tissues throughout the body, including adult bone marrow, compact bone, peripheral blood, adipose tissue, cord blood, amniotic fluid, foetal liver and other tissues (Erices et al., 2000; Young et al., 2001; De Ugarte et al., 2003). They have been defined as nonhaematopoietic, multipotent, stem-like cells capable of differentiating into both mesenchymal and nonmesenchymal lineages (Beyer Nardi and da Silva Meirelles, 2006).

MSCs are able to differentiate into osteoblasts, adipocytes and chondroblasts under standard in vitro differentiating conditions (Zhang et al., 2008). To date, there are no unique markers that can unequivocally identify MSCs and distinguish them from other cell types. However, it has been reported that MSCs express the surface antigens CD29, CD44, CD49, CD73,CD90, CD105, CD106, CD140b, CD166 and STRO-1 but are devoid of haematopoietic markers such as CD11b, CD14, CD19,CD31, CD34, CD45 and CD133 (Dominici et al., 2006; Roobrouck et al., 2008). Noel et al. (2002) described how MSCs in bone and cartilage can be identified by the absence of expression of CD34 and CD45 haematopoietic cell markers and showed they are positive for expression of CD90 and CD105. MSCs also express adhesion molecules, including VCAM (CD 106), ICAM (CD54) and LFA-3 (Majumdar et al., 2003), and are known to secrete interleukins such as IL-6, IL-7, IL-11, IL-12, IL-14, IL-15, leukaemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), stem cell factor (SCF) and FLT3 ligand (Majumdar et al., 1998). Expression by MSCs of several chemokines has been reported, including the receptor for SDF-1, CXCR4 (Honczarenko et al., 2006; Ponte et al., 2007; Sordi et al., 2005).

MSCs have been isolated from tissues in several pathological conditions, such as rheumatoid arthritis, peripheral blood of acute burns patients, obstructive apneas and bone sarcomas (Mansilla et al., 2006; Bian et al., 2009; Carreras et al., 2009). These studies suggest that MSCs isolated from different tissues have unique properties. We previously demonstrated that MSCs from bone marrow contain at least two subpopulations – one that expresses and one that lacks the stem cell marker aldehyde dehydrogenase 1 (ALDH1) – which exhibit different functional capacities (Korkaya et al., 2011b). Based on an aldefluor expression assay (STEM CELL technologies, BC, Canada), bone marrow-derived MSCs contain 5 – 6% aldefluor-positive cells, which are capable of generating both an aldefluor-positive and an aldefluor-negative MSC population. Aldefluor-positive MSCs show both adipogenic and osteogenic differentiation, but aldefluor-negative MSCs fail to do so under the same conditions. When co-cultured with breast cancer cells, an aldefluor-positive MSC population is able to regulate the CSC population (Liu et al., 2011). A recent study reported that MSCs can be polarized by downstream toll-like receptor (TLR) signalling into two homogenous phenotypes: MSC1 and MSC2 (Waterman et al., 2010). TLR4-primed MSC1 mostly elaborates proinflammatory mediators, while TLR3-primed MSC2 expresses mostly immunosuppressive responses. Furthermore, MSC1 and MSC2 have divergent effects on cancer growth and metastasis in in vitro assays and xenograft models (Waterman et al., 2012), with MSC1 primarily having an antitumour effect and MSC2 promoting tumour growth and metastases.

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