**4.2 Immunomodulatory effect**

To date, extensive literatures have demonstrated the therapeutic or ameliorative effects of MSCs on refractory and recurrent diseases via a bidirectional immunomodulatory approach [14, 25]. Notably, a variety of antiinflammatory factors and cytokines have been reported to play a pivotal role during inflammatory reactions such as interleukins (e.g., IL-6, IL-8, IL-10), transforming growth factor (TGF), stromal cellderived factor 1 (SDF-1), and vascular endothelial growth factor (VEGF) [22, 68, 69]. The underlying molecular mechanism lies in the sensitive response of MSCs toward the concentration gradient of inflammatory cytokines and chemokines [70]. As to OA, low-grade inflammation has been demonstrated critically in the pathogenesis, which therefore hinders the deposition of cartilage matrix at the damaged sites, delays the proliferation of osteoblast and chondrocytes, and thus resulting in low efficiency of articular cartilage repair [71, 72]. Currently, various kinds of immune cells have been observed in the synovium of OA, including the classically activated and proinflammatory macrophages (M1Mφ), antiinflammatory macrophages (M2Mφ), and T cells. For example, as the major counterparts of immune cells in the joints, Mφ can be hyperactivated by proinflammatory factors in OA patients such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and even the pathogen-associated

molecular patterns [73]. Therefore, the efficient treatment of OA should also pay close attention to the regulation of the local inflammatory microenvironment. As mentioned above, MSC with multilineage differentiation potential and effective immunomodulatory properties have been supposed as an alternative remedy in the administration of cartilage degradation [74]. In detail, MSCs are purposefully recruited to the site of the damaged cartilage and initiate the therapeutic effects upon osteochondral defects, and thus accelerating the reconstruction of articular surface in OA patients [70]. MSCs have been demonstrated involved in the regulation of M1Mφ towards M2Mφ via releasing growth and angiogenic factors as well as down-regulating inflammation and accelerating the remodeling of damaged tissue in OA. Additionally, the immunoregulatory effect of MSCs or MSC-derived EVs upon T cell subsets has also been extensively and in-detail described during the Th1/Th2 cell transformation, Th17 cell and Treg cell generation, and the apoptosis of hyperactivated T cells [75–79]. Similarly, state-of-the-art renewal has also indicated the immunomodulatory effect of MSCs upon CD24<sup>+</sup> CD38<sup>+</sup> B cells partially via soluble secreted factors. Interestingly, the role of MSC-derived EVs in mediating B-cell immunoregulation merit seems contradictory and still needs further investigation [67, 80].

#### **4.3 Autocrine and paracrine**

Autocrine and paracrine play a critical role in intercellular communications among MSCs and the adjacent osteochondral defects, which are at the cornerstone of regenerative medicine for MSC-based cytotherapy [81, 82]. The secreted substances such as cytokines and anti-inflammatory factors are responsible for the majority of the ascribed bioremediation via promoting the survival and proliferation of adjacent damaged cells and tissues. For example, mediators (e.g., VEGF, bFGF, IL-6, IL-8) in the conditioned media have been considered to play an important role in influencing the differentiation capacity of MSCs or cocultured cells through an autocrine loop [22, 23, 83]. Interestingly, Lee and colleagues have demonstrated that MSC-secreted PGE-2 plays a key role in the maintenance of self-renewal via EP2 receptor [84].

Of the indicated mode of action, the paracrine phenomenon has been widely recognized as the main benefit of MSC therapy based on the secreted factors acting on MSCs and the neighboring cells. Up to now, a variety of key factors have been isolated and verified including SDF-1, TGF, VEGF, prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the diversity in the constitutive secretome has also been put forward by pioneering investigators in the field [23, 84–86]. As to OA, MSC-derived exosomes or sEVs are supposed to effectively avoid the inherent risks of MSCs and thus hold rosy prospects in clinical applications [87, 88]. However, the inherent disadvantages such as low efficacy in preparations, rapid degradation and clearance still need sustained efforts for further improvement [33, 80].

#### **4.4 Direct- or trans-differentiation**

For the past decades, the differentiation potential including direct-differentiation and tans-differentiation has been recognized as the key avenue for MSC-based repair [81]. Of note, the differentiation of MSCs into osteoblasts and chondrocytes has been extensively reported as achievable according to the ISCT guidelines [17]. However, current updates in the field indicate that it is likely that paracrine rather than the direct-differentiation or trans-differentiation play a core role in cartilage repair of OA *Mesenchymal Stem Cell-based Cytotherapy for Osteoarthritis Management: State of the Art DOI: http://dx.doi.org/10.5772/intechopen.108258*

after MSC delivery because intrathecal injection has presented limited MSC retention and engraftment. For example, aw we previously reviewed, initial attempts upon the molecular mechanisms for disease treatment with MSC transplantation focused on seeking direct evidence for generating functional cells during the rehabilitation of damaged tissues, whereas it was found to be difficult by most investigators when considering the insufficiency of effective retention rate (<5%) [89]. Instead, based on the unique homing property, MSCs mainly migrate to the damaged tissues and perform the restorative function through an orchestration of modulation, which is further verified with the aid of fluorescence *in situ* hybridization [90].
