**3.3 MSC: immunomodulatory potential**

The paracrine effects of MSCs may have great importance in the treatment of autoimmune diseases. Through the secretion of bioactive molecules, MSCs have the capacity of regulating immune responses. These cells can regulate adaptive immune responses through multiple redundant pathways, interacting with various immune cells and secreting soluble mediators such as IL-6, IL-10, prostaglandin E2 (PGE2), nitric oxide (NO), transforming growth factor-β1 (TGF-β1), and hepatocyte growth factor (HGF), indoleamine-pyrrole 2, 3-dioxygenase (IDO) [58, 59]. They can regulate APCs activity, decreasing maturation and proliferation of DCs [14]. MSC also may regulate macrophage activity by polarizing its pro-inflammatory phenotype (M1) to its anti-inflammatory phenotype (M2) [15]. Therefore, suppress T cell proliferation and activation and regulate the differentiation of Th cells and act on the humoral response by inhibiting of B cell activation and antibody production [60]. MSCs may also reduce pro-inflammatory cytokines proliferation, such TNF-α, which has an important role of the pathogenesis of autoimmune diseases and chronic inflammation (**Figure 1)** [14, 16, 61].

#### **Figure 1.**

*Benefits of MSCs paracrine effect (immunomodulatory) on immune cells imbalance. MSCs secrete many soluble mediators, including anti-inflammatory cytokines stimulation that regulates APCs functions capable to decrease proliferation of DCs and regulate macrophage activity by polarizing proinflammatory phenotype (M1) to anti-inflammatory phenotype (M2). Therefore, they are responsible for humoral response regulation by the decrease of B cells proliferation and antibodies production. The APCs are also capable to regulate the T cell activities as well as inhibit cytotoxic T cell proliferation and upregulation and increase of Treg cells. MSCs may also promote the decrease of proinflammatory cytokines secretion. And act on the homing regulation of HSCs mechanism on stages of adhesion, expansion, and migration through chemokine and other factors secretion.*

## **4. MSC mechanism in AA treatment**

The first paracrine effect, showed for MSCs, was the capacity to support HSCs growth *in vitro*. Afterward, adipose tissue (AT) – derived MSCs also supported HSCs growth *in vitro* [62, 63]. Therefore, the most successful clinical application of MSCs is involved in the hematological disease.

At BM microenvironment, MSCs niche supports hematopoietic cells and produce factors recruiting HSCs and supporting hematopoiesis [64]. This mechanism occurs through chemokine secretion of C-X-C motif chemokine ligand 12 (CXCL12), which acts on the homing regulation of HSCs, regulating the stages of adhesion, expansion and migration [65, 66]. The secretion of other factors is also important in the proliferation of HSCs mechanisms such as Flt-3 ligand (FLT3LG) [67], thrombopoietin (TPO) [68] and IL-6 [17]. That despite being a proinflammatory cytokine in general, when IL-6 is secreted in BM microenvironment, is capable to stimulate hematopoiesis [69, 70].

More recently, the studies showed that the main cause of AA is autoimmunity. This process occurs in the result of an imbalance between CD8 + and CD4 + T cells, including Th1, Th2, Th17, NK, leading to the death of hematopoietic cells and their precursors [28]. Many studies have hypothesized that the onset of the immune imbalance in AA begins by stimulating APCs through an unknown antigen resulting in the T cells activation [71]. Another important mechanism of MSCs is the immunomodulation mechanism. MSCs can act directly on AA imbalance by T cells suppression, inhibiting activation and proliferation of T cells [72]. MSCs also inhibit the secretion of two important cytokines present in the pathology of AA, the

**155**

type 1 matrix metalloproteinase [81].

*Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment*

Immunomodulatory effect: Decreased secretion of proinflammatory cytokines, ↓IFN-γ ↓TNF-α ↓IL-17 ↓IL-2;

Regulation of T cell activity and Treg cell proliferation

↓ Cytotoxic T cell ↑Treg

↓ Apoptosis

↓ B cells

*MSC can decrease secretion of pro-inflammatory cytokines such as TGF, IFN-γ TNF-α, IL-17, regulate T cell activity, inhibit proliferation of cytotoxic T cells and stimulate Treg activity. MSC has anti-apoptotic properties, protects BM environment and recovery BM through cytoprotective effect and stimulates macrophages M2 activation and hematopoiesis improvements. MSCs may also regulate APCs functions, humoral response, and cytotoxicity of NK cells.*

Protect BM by antiapoptotic properties

↓ DCs maturation and proliferation and ↓ Macrophages M1 activation ↑ Macrophages M2 activation

↑ Hematopoiesis improvements ↑ CXCL12 ↑FLT3LG ↑TPO ↑IL-6

Regulate APCs functions

Regulate humoral response

↓ Antibodies production

↓ Cytotoxicity of NK cells

INF-γ and TNF-α and stimulate the proliferation of Treg, promoting the production of the anti-inflammatory cytokine IL-10 **Table 1** [73, 74]. In addition, some studies

In the last years, several studies have been exploring intravenous administrations (IV) due to being safe and do not present morbidity risk for patients. However, still lack the data about the biodistribution mechanism of MSCs and about how these cells engraftment on the target organ, which is essential for the success of clinical studies. It is known that the biodistribution is influenced in vivo and in vitro conditions. Stromal cell-derived factor 1 (SDF-1) (also known as CXCL12) is upregulated at sites of injury and acts as a chemoattractant to recruit circulating or residing MSCs expressing its cognate receptor CXC chemokine receptor 4 (CXCR4). It has been demonstrated that the CXCR4-SDF-1 axis is critical for BM homing [76]. Diverse studies demonstrate that some in vitro conditions may influence the expression of adhesion molecules [77, 78]. For instance, long expansion periods [79] and cells culturing at high density may reduce CXCR4 cell expression; the cells cultured at higher confluence secrete more metalloproteinase inhibitor 3, which decreases migration of MSCs when compared to those cultured at the low confluence [80]. Hypoxia condition may increase CXCR4 expression; on the other hand, hypoxia may decrease matrix metalloproteinase-2 secretion and an increase in membrane-

In vivo engraftment is influenced by interactions of MSCs with different types of immune cells that depend on their ability to respond to signals from the immune

also show that MSCs also acts through its anti-apoptotic effects [75].

*Table shows disorders characterized in AA and the mechanism of action of MSCs in AA pathology.*

**5. Biodistribution and engraftment of allogeneic MSC in BM**

*DOI: http://dx.doi.org/10.5772/intechopen.89090*

Aberrant secretion of pro-inflammatory cytokines ↑IFN-γ ↑TNF-α ↑IL-17 ↑IL-2;

Imbalance between CD8+ and CD4+ T cells; ↑ Cytotoxic T cell ↓Treg

Apoptosis of HSC and progenitor cells

Abnormal APC activation ↑ DCs ↑ Macrophage

Abnormal humoral response

Irregular activity of NK cells ↑ Cytotoxicity of NK cells

↑ Antibodies production

BM hypoplasia Recovery of BM

↑ Apoptosis

↑ B cells

**Table 1.**

**AA disorders x MSC benefits**

*Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment DOI: http://dx.doi.org/10.5772/intechopen.89090*


*MSC can decrease secretion of pro-inflammatory cytokines such as TGF, IFN-γ TNF-α, IL-17, regulate T cell activity, inhibit proliferation of cytotoxic T cells and stimulate Treg activity. MSC has anti-apoptotic properties, protects BM environment and recovery BM through cytoprotective effect and stimulates macrophages M2 activation and hematopoiesis improvements. MSCs may also regulate APCs functions, humoral response, and cytotoxicity of NK cells.*

#### **Table 1.**

*Human Blood Group Systems and Haemoglobinopathies*

**4. MSC mechanism in AA treatment**

MSCs is involved in the hematological disease.

to stimulate hematopoiesis [69, 70].

The first paracrine effect, showed for MSCs, was the capacity to support HSCs growth *in vitro*. Afterward, adipose tissue (AT) – derived MSCs also supported HSCs

*Benefits of MSCs paracrine effect (immunomodulatory) on immune cells imbalance. MSCs secrete many soluble mediators, including anti-inflammatory cytokines stimulation that regulates APCs functions capable to decrease proliferation of DCs and regulate macrophage activity by polarizing proinflammatory phenotype (M1) to anti-inflammatory phenotype (M2). Therefore, they are responsible for humoral response regulation by the decrease of B cells proliferation and antibodies production. The APCs are also capable to regulate the T cell activities as well as inhibit cytotoxic T cell proliferation and upregulation and increase of Treg cells. MSCs may also promote the decrease of proinflammatory cytokines secretion. And act on the homing regulation of HSCs mechanism on stages of adhesion, expansion, and migration through chemokine and* 

More recently, the studies showed that the main cause of AA is autoimmunity. This process occurs in the result of an imbalance between CD8 + and CD4 + T cells, including Th1, Th2, Th17, NK, leading to the death of hematopoietic cells and their precursors [28]. Many studies have hypothesized that the onset of the immune imbalance in AA begins by stimulating APCs through an unknown antigen resulting in the T cells activation [71]. Another important mechanism of MSCs is the immunomodulation mechanism. MSCs can act directly on AA imbalance by T cells suppression, inhibiting activation and proliferation of T cells [72]. MSCs also inhibit the secretion of two important cytokines present in the pathology of AA, the

growth *in vitro* [62, 63]. Therefore, the most successful clinical application of

At BM microenvironment, MSCs niche supports hematopoietic cells and produce factors recruiting HSCs and supporting hematopoiesis [64]. This mechanism occurs through chemokine secretion of C-X-C motif chemokine ligand 12 (CXCL12), which acts on the homing regulation of HSCs, regulating the stages of adhesion, expansion and migration [65, 66]. The secretion of other factors is also important in the proliferation of HSCs mechanisms such as Flt-3 ligand (FLT3LG) [67], thrombopoietin (TPO) [68] and IL-6 [17]. That despite being a proinflammatory cytokine in general, when IL-6 is secreted in BM microenvironment, is capable

**154**

**Figure 1.**

*other factors secretion.*

*Table shows disorders characterized in AA and the mechanism of action of MSCs in AA pathology.*

INF-γ and TNF-α and stimulate the proliferation of Treg, promoting the production of the anti-inflammatory cytokine IL-10 **Table 1** [73, 74]. In addition, some studies also show that MSCs also acts through its anti-apoptotic effects [75].
