Mesenchymal Stromal Cells: From Bone Marrow to Neoplastic Disorders

Review Article

J Blood Disord. 2014;1(3): 5.

Mesenchymal Stromal Cells: From Bone Marrow to Neoplastic Disorders

Giuseppina Divisato and Fernando Gianfrancesco

Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Italy

*Corresponding author: Fernando Gianfrancesco, Institute of Genetics and Biophysics "Adriano Buzzati- Traverso", National Research Council of Italy, Naples, Italy.

Received: October 20, 2014; Accepted: November 06, 2014; Published: November 07, 2014


Mesenchymal stromal cells (MSCs) represent a small and heterogeneous subpopulation of mesenchymal stem cells that possesses multilineage differentiation potential. These cells are mainly present in bone marrow, but also in other tissues, and represent a valuable resource for their ability to differentiate into different cell lines and for many therapeutic approaches. MSCs are able to differentiate into cells of mesodermal origin such as adipocytes, chondrocytes, osteoblasts or fibroblasts and in vitro also into cells of non-mesodermal lineages. In bone marrow, they establish the microenvironment for the growth and differentiation of the hematopoietic stem cells (HSCs) resulting crucial for HSC maintenance and haematopoiesis. Nevertheless, the proliferation and/or the survival rate of MSCs may contribute to the onset of different types of bone sarcomas, such as Osteosarcoma, Chondrosarcoma and Giant Cell Tumor of Bone that represent the result of neoplastic degeneration of their corresponding committed mesenchymal precursors, probably as a consequence of the alteration of different or common biochemical pathways.

Keywords: Mesenchymal stromal cells; Bone marrow; Neoplastic disorders; Stem cells; FGFRs

Bone Marrow and Stem Cell Niches

Bone plays an essential role in the structure and movement of the body, and consists of cells (osteoclasts and osteoblasts) at different developmental stages, collagen fibrils, and mineral deposits such as calcium and phosphate. The bone cavity is filled with soft bone marrow that is the primary postnatal site of several stem cells including those of haematopoietic (HSC) and mesenchymal (MSC) lineages [1-5]. The stem cell niche represents the microenvironment created by supporting cells and their signals, in which stem cells reside and undergo self-renewal and differentiation [6-7]. The ability of adult stem cells to self-renew and differentiate is a critical point for tissue homeostasis: the depletion of this population occurs as a consequence of boosted self-renewal rate. On the other hand, the uncontrolled expansion of stem cell population, could promote tumorigenesis. The quiescence of stem cells within the niche is essential, about 70% of which are in the G0 phase of the cell cycle. Particularly, it has been shown that approximately 30% of the quiescent HSC divide every 145-193 days (protecting them from DNA damage by limiting the number of their cellular divisions), while a more active subpopulation divides every 28-36 days [8]. One mechanism that ensures the balance between self-renewal and differentiation processes is the control of asymmetric/symmetric stem cell division. In asymmetric division the stem cells divide into 2 daughter cells: one daughter cell remains in the niche as a stem cell and the other leaves the niche to produce a committed cell population. In symmetric division stem cells divide into 2 identical daughter cells that remain both in the niche as stem cells. The last decade has witnessed an increasing interest in stem cell niches, even if the numbers of niches in bone marrow, their cellular composition as well as their interactions are yet to be clearly determined [6,9-15]. The biochemical pathways promoting MSCs commitment are activated by micro-environmental conditions that include hormones (PTH, vitamin D3 and estrogen), growth factors (BMPs, TGFβs, IGF), and mechanical stimuli. In addition, there is an increasing interest in the role of non-coding RNAs (miRNAs) as well as of epigenetic mechanisms regulating the differentiation fate of MSC [16-18].

Mesenchymal Stromal Cell Differentiation

Haematopoietic stem cells mainly reside within the bone marrow, which is the primary site of HSC maintenance and haematopoiesis and also contains many other different non-haematopoietic cell types (Figure 1). Stromal and differentiated cells (chondrocytes, osteoblasts, fibroblasts, adipocytes) compose this microenvironment, normally referred as stroma [19,20]. Particularly, mesenchymal stromal cells that are committed toward osteoblast lineage express bone sialoprotein, osteonectin, osteopontin, osterix and Runx2 (runt-related transcription factor 2) [21]. Many different biochemical pathways drive this osteoblast differentiation program including FGFs (fibroblast growth factors) and WNTs signaling [22,23]. Specifically, FGF receptor ligands are involved in proliferation and osteoblast differentiation of mesenchymal precursors and therefore in bone deposition, through the interaction with four type of fibroblast growth factor receptors (FGFRs) [24,25]. FGFR3 and FGFR4 are involved in the differentiation of chondrocytes. On the other hand FGFR1 is involved in osteoblast proliferation while FGFR2 promotes osteoblast differentiation of mesenchymal stem cells promoting Runx2 expression and inhibiting TWIST1 [26,27]. Also Wnt signalling is involved in MSCs proliferation and in the regulation of the osteogenic differentiation [28]. Canonical Wnt signaling can be activated by the interaction of several secreted Wnt ligands with frizzled receptors and with the co-receptor Lipoprotein Receptor Related Protein 5/6 (LRP5/6). Wnt activation, involves different effectors such as β-catenin, JNK and calcium-channels regulators. Cytoplasmatic β-catenin accumulation and its nuclear translocation promote the activation of several oncogenes (e.g., c-Myc) and of different metalloproteinases, promoting extracellular matrix (ECM) degradation and cellular invasion and migration [29]. Wnt3a ligand has a modulatory function in chondrogenesis through bone morphogenetic protein (BMP)-2 expressions; Wnt7a enhances chondrogenesis through various TGFB1-MAPK signaling pathways; and Wnt1 inhibits chondrogenesis promoting TWIST1 up regulation [30].

Citation: Divisato G and Gianfrancesco F. Mesenchymal Stromal Cells: From Bone Marrow to Neoplastic Disorders. J Blood Disord. 2014;1(3): 1014. ISSN 2379-8009