8.3. Cellular components

The expression of α-smooth muscle actin (α SMA) in MSCs from all tissue types tested, is the basis of a perivascular nature of the MSC niche [53] and the immunohistochemical localization of CD45/CD31/Sca-1+/Thy-1+ cells to perivascular sites [54]. These cells also expressed α SMA and some even expressed 3G5, a pericyte-associated cell-surface marker. Doherty et al. [55] suggested that pericytes are in fact MSCs, because their differentiation into osteoblasts, chondrocytes, and adipocytes. MSCs have easy access to all tissues and participate in healing of many different tissues due to their presence in perivascular niches throughout the body.

Cadherins, MSCs transmembrane proteins responsible for cell–cell adhesion, polarity, differentiation, migration [18], interact with Wnts, which implicates in the biology of other stem cell niches [56].

### 8.4. Soluble components

The nature of bone marrow milieu is hypoxic. Comparison of human MSCs proliferative capacity was better maintained in the former when cultured in hypoxic versus normoxic conditions (2 and 20% oxygen). Additionally, hypoxia has doubled the number of existing CFU-Fs, as well as enhanced the expression of rex-1and oct-4; genes which are expressed by embryonic stem cells and are crucial in maintaining 'stemness'. Therefore, through increasing the plasticity and the proliferative capacity of MSCs, hypoxia is considered to have a double effect. However, the mechanism of action of hypoxia on MSCs is still unknown, although there is a possibility through the oct-4 upregulation by the transcription factor hypoxia-induced factor-2α (HIF-2α) [57].

The effect of proteins secreted in the MSC niche is unexplained. The cell types studied have either induced differentiation or had no effect on MSCs. Finding soluble proteins permitting proliferation while inhibiting MSC differentiation would be ideal for simulating the niche and for MSCs expansion ex vivo.

#### 8.5. Extracellular matrix components

However, ECM alone can regulate MSC differentiation, with potential applications for tissue engineering, no specific matrix components have been isolated to maintain MSCs in their naïve state, as a niche matrix would do. For example, osteoblasts on titanium scaffolds leave ECM after decellularization increasing osteogenesis markers, such as alkaline phosphatase and calcium deposition, in MSCs [58]. The ability to design artificial matrices that can resemble the tissue microenvironment in vivo and control the appropriate differentiation of stem cells is a promising approach to therapeutic applications. Molecular information on ECM–MSC interactions, involving integrins, which involved in niche biology in other systems [59], is clearly needed.
