**1. Introduction**

Stem cells are undifferentiated cells possessing greater capacity of self-renewal and multilineage differentiation potential. This makes them unique candidates for curing a diverse variety of human degenerative diseases. Based on their potency, stem cells are classified into three broad groups: embryonic stem cells (ESCs), fetal stem cells (FSCs), and adult stem cells (ASC). ESCs are pluripotent stem cells isolated from inner cell mass of blastocysts of human embryos. The uniqueness of ESCs lies in the fact that they are capable of differentiation into all three primary germ layers, i.e., ectoderm, endoderm, and mesoderm. However, due to high tendency of teratoma formation and ethical issues regarding the destruction of human embryos, the clinical applications of ESCs are restricted. Alternatively, fetal and adult tissue-derived stem cells are gaining popularity with little ethical

concerns. Fetal stem cells can be isolated from extraembryonic tissues like cord blood, amniotic fluid, Wharton's jelly, the placenta, and amniotic membrane [1–3]. However, adult stem cells (ASCs) are multipotent cells and are usually harvested from the bone marrow, adipose tissue, dental pulp, etc. All together, these cells possess clonogenic and self-renewing potential and plasticity to differentiate and often transdifferentiate into different tissue types.

Isolated stem cells from both adult and fetal tissues are multipotent and are recognized as MSCs. Notably, despite similar morphology and phenotypic properties, these tissue-specific MSCs have subtle differences in their regenerative potential due to the impact of stem cell niche on cell fate, known as stem cell niche theory, genetic variability, and/or epigenetic alterations [4]. Several studies have been carried out to show that there are differences in regenerative capacity of MSCs populations of

#### **Figure 1.**

*A diagrammatic representation of cellular characteristics, mode of action, and their therapeutic potential of mesenchymal stem cells with current status of clinical trial.*

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*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions*

the same passage number that have been isolated from different pockets of the body [5]. A recent comprehensive report also supports the hypothesis that tissue-specific MSCs express certain source-specific markers [6]. Dominic et al. established criteria to define MSCs on the basis of the following characteristics: (1) plastic-adherent cells; (2) expression of surface markers, CD73, CD90, CD105, and HLA-ABC, but negative expression from hematopoietic lineage-specific markers, CD34, CD45, CD14, CD11b, CD19, or HLA-DR; and (3) potential to differentiate into trilineage,

Due to their enhanced regenerative potential, the use of MSCs has become an emerging strategy for the treatment of injured or degenerated tissues. It was observed that in in vivo scenario, MSCs showed profound immunomodulatory effect [8]. The most important characteristic of MSCs is its immunomodulatory property which augments and modulates both adaptive and innate immune

MSCs are also known for their immune-privileged property due to their low immunogenicity. Human MSCs show low levels of human leukocyte antigen (HLA) class I, and they do not express HLA-DR which is necessary to escape immune surveillance. The presence of HLA class I is important as low levels of HLA class I protect cells from the natural killer (NK) cell-mediated cytotoxicity. On the contrary, cells which do not express HLA class I are targeted and destroyed easily. Another essential characteristic is that they home and migrate to the site of damage where there is secretion of inflammatory chemokines. These events are mediated by several chemokine receptors which aid in their migration and homing potential to the sites of inflammation [9]. Owing to the immune tolerance property of MSCs, they possess several clinical advantages due to which these cells are also referred as "universal donors" [10, 11]. However, as true with any other cell-based therapy, the evaluation of safety and efficacy of these MSCs in allogeneic strategies for clinical

The initial reports of immunoregulatory properties were started with bone marrow-derived MSCs (BM-MSCs) [12]. Later, other sources of MSCs such as adipose tissue-derived MSCs (AD-MSCs) and Wharton's jelly-derived MSCs (WJ-MSCs) were also explored for their immunomodulatory properties [1]. However, several challenges need to be overcome prior to the clinical applications of MSCs. Hence, a thorough insight of the various biological properties of MSCs will elucidate the mechanisms of MSC-based transplantation for

**2. Immunoregulatory function of MSCs in the inflammatory** 

A key factor of survival in multicellular organisms is the maintenance and balance of homeostatic state. In the absence of inflammation, phagocytic cell is recruited to remove the apoptotic cells, whereas during acute injury, it is accompanied by inflammation, and the cell components that are released from necrotic cells result in microvascular damage due to increased vasopermeability and infiltration of macrophages and neutrophils [13]. During the process of phagocytosis of necrotic cells, there is secretion of pro-inflammatory mediators such as interleukin-1 (IL-1), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), various chemokines which further initiate downstream signaling pathways [14]. Adaptive immune response actively participates in the repair of damaged tissues in close association with CD4+, CD8+, T, and B cells [13]. Recently, MSCs have been recognized to be actively involved in damaged tissue repair processes. As a functional unit for

*DOI: http://dx.doi.org/10.5772/intechopen.80772*

i.e., osteoblast, adipocytes, and chondrocytes [7].

responses as it initiates the wound healing paradigm.

use is of utmost importance (**Figure 1**).

immunomodulation.

**microenvironment**

#### *Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions DOI: http://dx.doi.org/10.5772/intechopen.80772*

the same passage number that have been isolated from different pockets of the body [5]. A recent comprehensive report also supports the hypothesis that tissue-specific MSCs express certain source-specific markers [6]. Dominic et al. established criteria to define MSCs on the basis of the following characteristics: (1) plastic-adherent cells; (2) expression of surface markers, CD73, CD90, CD105, and HLA-ABC, but negative expression from hematopoietic lineage-specific markers, CD34, CD45, CD14, CD11b, CD19, or HLA-DR; and (3) potential to differentiate into trilineage, i.e., osteoblast, adipocytes, and chondrocytes [7].

Due to their enhanced regenerative potential, the use of MSCs has become an emerging strategy for the treatment of injured or degenerated tissues. It was observed that in in vivo scenario, MSCs showed profound immunomodulatory effect [8]. The most important characteristic of MSCs is its immunomodulatory property which augments and modulates both adaptive and innate immune responses as it initiates the wound healing paradigm.

MSCs are also known for their immune-privileged property due to their low immunogenicity. Human MSCs show low levels of human leukocyte antigen (HLA) class I, and they do not express HLA-DR which is necessary to escape immune surveillance. The presence of HLA class I is important as low levels of HLA class I protect cells from the natural killer (NK) cell-mediated cytotoxicity. On the contrary, cells which do not express HLA class I are targeted and destroyed easily. Another essential characteristic is that they home and migrate to the site of damage where there is secretion of inflammatory chemokines. These events are mediated by several chemokine receptors which aid in their migration and homing potential to the sites of inflammation [9]. Owing to the immune tolerance property of MSCs, they possess several clinical advantages due to which these cells are also referred as "universal donors" [10, 11]. However, as true with any other cell-based therapy, the evaluation of safety and efficacy of these MSCs in allogeneic strategies for clinical use is of utmost importance (**Figure 1**).

The initial reports of immunoregulatory properties were started with bone marrow-derived MSCs (BM-MSCs) [12]. Later, other sources of MSCs such as adipose tissue-derived MSCs (AD-MSCs) and Wharton's jelly-derived MSCs (WJ-MSCs) were also explored for their immunomodulatory properties [1].

However, several challenges need to be overcome prior to the clinical applications of MSCs. Hence, a thorough insight of the various biological properties of MSCs will elucidate the mechanisms of MSC-based transplantation for immunomodulation.
