Table 1: The cytokines secreted by MSCs that regulate HSCs. Function Regulate the adhesion, expansion, migration, and homing of HSCs Reduce the production of inﬂammatory cytokines and chemokines Maintain HSC proliferation and self-renewal, regulate hematopoietic growth Inﬂuence HSC proliferation and diﬀerentiation Regulate HSC engraftment Maintain HSC proliferation and self-renewal Regulate hematopoietic growth Regulate HSC engraftment Regulate HSC homing and adhesion References [10, 11, 28–32] [33] [28] [29, 34] [35] [28, 36] [35] [35, 37] 2 Cytokines CXCL12 (SDF-1) FL IL-6, TPO GM-CSF SCF VCAM1, E-selectin, collagen I, ﬁbronectin MSCs can be cotransplanted with HSCs to improve their engraftment [25–27] (Table 1). 2. Mesenchymal Stem Cells Contribute to Hematopoietic Stem Cell Niche The term “niche” for the speciﬁc HSC BM microenviron- ment was ﬁrst coined in 1978, proposing that HSCs are in intimate contact with the bone, which was responsible for the apparently unlimited capacity of HSCs’ proliferation and the inhibition of HSCs’ maturation [38]. Niches exist within the BM which preserve speciﬁc aspects of hematopoiesis, such as HSC survival, self-renewal, and diﬀerentiation, supporting the maintenance of the blood system under normal and stressed conditions [39]. Research has made it increasingly clear that the stem cell niches provide a microenvironment which is important in protecting the self-renewing, undiﬀerentiated state of their residents [40]. Three types of HSC niches have been hypothesized, deﬁned according to the HSC uniformity [18, 41]. Two of these proposed niches are provided by cells directly descending from MSCs: the osteoblastic niche, where HSCs reside in close contact with endosteal cells [8], and the reticular stromal niche, where HSCs reside in close contact with stromal cells which are also known as mural cells or pericytes, the smooth muscle cells lining arteriolar side of the sinusoids [42]. The third proposed niche is the vascular/sinusoidal niche, where HSCs reside in direct contact with endothelial cells in the venous side of the sinusoids [43]. It is well known that HSC circulation involves HSCs leaving the BM, entering the vascular system (mobilization), and returning to the BM (homing) [44, 45]. The BM vascular structure provides a barrier between the hematopoietic compartment and the peripheral circulation. Most primitive HSCs remain Bone Marrow Research physiologically quiescent within the BM niche; however, a portion of HSCs leave this resting pool and start the process of mobilization [39, 46–48]. Studies showed that both mouse and human osteoblast cell lines secreted a large number of cytokines that promote the proliferation of haematopoietic cells in culture, prov- ing that cells involved in bone formation have stem-cell- supporting activity [49, 50]. MSCs reside in the bone cavity and are proposed to give rise to the majority of marrow stromal cell lineages, including chondrocytes, osteoblasts, and adipocytes, as suggested in numerous studies [48–50]. MSCs and HSCs form a structurally unique niche in the BM, which is regulated by local input from the surrounding microenvironment, and long-distance cues from hormones and the autonomic nervous system [51]. MSCs isolated from BM produce several growth factors and chemokines, such as CXCL12 (SDF-1), stem cell factor (SCF), Flt-3 ligand (FL), thrombopoietin (TPO), interleukin (IL)-6, IL- 11, leukemia inhibitory factor (LIF), macrophage colony- stimulating factor (M-CSF), tumor necrosis factor- (TNF-) α, and transforming growth factor- (TGF-) β1 [28, 52–54]. HSCs are reduced in the BM after the depletion of MSCs, owing at least in part to mobilization towards extramedullary sites [51]. Loss of SCF from supporting cells or the receptor in HSCs leads to hematopoietic failure, indicating MSCs play an essential role in HSC niche function [36]. SCF and FL are implicated in maintaining HSC proliferation and self-renewal, regulating hematopoietic growth [28]. IL- 3 or IL-6 combined with TPO signaling can inﬂuence HSC proliferation and diﬀerentiation [29, 34]. Besides, as mentioned previously, the chemokine CXCL12 interacts with its receptor CXCR4, regulates the cyclical release of HSCs, the migration of HSCs to the vascular niche from BM, and the homing of HSCs to the BM [10, 11, 29–32], and promotes adhesive interactions between HSCs and stromal cells [55]. In addition, CXCL12 chemokine signaling pathway contribute to the ex vivo expansion of HSCs [28]. Moreover, CXCL12 mediates angiogenic responses, promotes diﬀeren- tiation of CD34+ cells to endothelial progenitor cells, and appears to aﬀect many other factors, including G-CSF, VEGF, and CXCL16 that relate to HSC mobilization and homing [33]. However, only β-catenin-activated MSCs but not na¨ıve MSCs have stimulatory eﬀect on HSC self-renewal in vivo [56]. 3. The Effect of Mesenchymal Stem Cell on the Maintenance of Hematopoietic Stem Cells Coculture of HSCs with MSCs might be an ideal method for maintaining the HSC pluripotency, because the growth or survival signals might be transferred to the HSC via adhesive molecules by modulating the cytokines and growth factor-dependent signals [57]. 5-aza-deoxycytidine (aza-D) and trichostatin A (TSA) have potent activity to maintain the stemness of HSCs, being candidate additives for HSCs ex vivo expansion, but they can also cause serious cell death [58, 59]. Koh et al. examined the eﬀects of MSCs on the maintenance of CD34+ cells driven by aza-D and TSA in culture with the combined cytokines, and found that the total cell number