**1. Introduction**

Mesenchymal stem cells (a.k.a. mesenchymal stromal cells, MSCs) hold enormous promise as a durable, sustainable, and novel cell-based biologic therapeutic for a diverse range of clinical applications aimed at preventing or reversing organ injury and promoting tissue regeneration.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Substantial data have accumulated regarding the safety of administering both autologous and allogeneic MSCs to patients with a broad array of diseases. In addition, it is increasingly clear that MSCs exert anti-fibrotic, pro-angiogenic, regenerative, and immunomodulatory effects, and therefore, offering therapeutic potential in a wide range of presently untreatable conditions. The growing evidence supporting the use of MSCs as therapeutic strategy includes their relative ease of isolation and expansion in culture, multilineage differentiation capacity, immunomodulatory, anti-inflammatory, anti-microbial, and regenerative effects, homing and migratory capacity to injury sites, safety profile in allogeneic transplantation, and few ethical considerations [1, 2]. The use of large animal models in preclinical studies has been instrumental in deciphering the underlying mechanisms of action of MSC therapy [3]. Moreover, substantial human phenotypic data has demonstrated that MSC therapy is safe [4–10] and holds the potential for repair and regeneration of diverse organ systems and amelioration of multiple chronic illnesses for which there is currently no cure [4, 6, 7, 9–24]. There are currently various MSC sources under investigation in preclinical and clinical studies, namely bone marrow, adipose tissue, umbilical cord blood, umbilical cord, and amniotic membranes/placenta (**Figure 1**). Multiple mechanisms of action underlie successful MSC therapy, including MSC engraftment and differentiation, and more importantly, the secretion of bioactive paracrine molecules that inhibit apoptosis, fibrosis, and inflammation and promote neovascularization/neo-angiogenesis and endogenous stem cell recruitment, proliferation, and differentiation [25–27] (**Figure 2**). In particular, cell-cell interactions between MSCs

and endogenous host cells within stem cell niches provide structural support and produce the soluble signals that regulate stem cell function in tissues[1, 28–30] (**Figure 1** inset). An indepth molecular understanding of how MSCs produce the therapeutic benefits demonstrated in numerous clinical trials is critical for the development and design of new clinical trials as well as for the development of newer generations of MSC products that have greater efficacy and sustainability. This chapter will review the current state of knowledge in the use of MSCs

Mesenchymal Stromal Cells as a Therapeutic Intervention

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MSCs are non-hematopoietic stem cells with multilineage potential that originate from the mesodermal germ layer. The pioneering studies conducted by Friedenstein et al. provided the first evidence that these fibroblast-like cells, described as spindle-shaped and clonogenic in culture conditions could be isolated from bone marrow via their inherent adherence to plastic in culture [31, 32]. MSCs are an integral part of the stromal microenvironment and support hematopoietic stem cells and regulate hematopoiesis, although they comprise only ~0.01–0.001% of the total nucleated cells in the bone marrow [33, 34]. Moreover, MSCs have been isolated from virtually every tissue type, including adipose tissue, liver, lung, skeletal and heart muscle, synovial membrane, amniotic fluid, placenta, umbilical cord blood, and

as a therapeutic strategy for organ structural and functional repair.

dental pulp, suggesting that they reside in all organs [35–37].

**2. Biology of mesenchymal stem cells**

**Figure 2.** Mechanism of action of mesenchymal stem cell therapy.

**Figure 1.** Mesenchymal stem cell tissue sources, ex vivo expansion, and role in stem cell niche. Initially identified in bone marrow, MSCs can be isolated from various tissues in the body. To isolate MSCs from a bone marrow biopsy, first the mononuclear cells are isolated from red blood cells by Ficoll density centrifugation, and subsequently, the MSCs are separated from the mononuclear cells by plastic adherence in culture. Inset: the constituents of a stem cell niche are depicted in this schematic. ECM extracellular matrix. *Adapted from Wagers AJ et al., Cell Stem Cell, 2012*.

**Figure 2.** Mechanism of action of mesenchymal stem cell therapy.

Substantial data have accumulated regarding the safety of administering both autologous and allogeneic MSCs to patients with a broad array of diseases. In addition, it is increasingly clear that MSCs exert anti-fibrotic, pro-angiogenic, regenerative, and immunomodulatory effects, and therefore, offering therapeutic potential in a wide range of presently untreatable conditions. The growing evidence supporting the use of MSCs as therapeutic strategy includes their relative ease of isolation and expansion in culture, multilineage differentiation capacity, immunomodulatory, anti-inflammatory, anti-microbial, and regenerative effects, homing and migratory capacity to injury sites, safety profile in allogeneic transplantation, and few ethical considerations [1, 2]. The use of large animal models in preclinical studies has been instrumental in deciphering the underlying mechanisms of action of MSC therapy [3]. Moreover, substantial human phenotypic data has demonstrated that MSC therapy is safe [4–10] and holds the potential for repair and regeneration of diverse organ systems and amelioration of multiple chronic illnesses for which there is currently no cure [4, 6, 7, 9–24]. There are currently various MSC sources under investigation in preclinical and clinical studies, namely bone marrow, adipose tissue, umbilical cord blood, umbilical cord, and amniotic membranes/placenta (**Figure 1**). Multiple mechanisms of action underlie successful MSC therapy, including MSC engraftment and differentiation, and more importantly, the secretion of bioactive paracrine molecules that inhibit apoptosis, fibrosis, and inflammation and promote neovascularization/neo-angiogenesis and endogenous stem cell recruitment, proliferation, and differentiation [25–27] (**Figure 2**). In particular, cell-cell interactions between MSCs

144 Stromal Cells - Structure, Function, and Therapeutic Implications

**Figure 1.** Mesenchymal stem cell tissue sources, ex vivo expansion, and role in stem cell niche. Initially identified in bone marrow, MSCs can be isolated from various tissues in the body. To isolate MSCs from a bone marrow biopsy, first the mononuclear cells are isolated from red blood cells by Ficoll density centrifugation, and subsequently, the MSCs are separated from the mononuclear cells by plastic adherence in culture. Inset: the constituents of a stem cell niche are

depicted in this schematic. ECM extracellular matrix. *Adapted from Wagers AJ et al., Cell Stem Cell, 2012*.

and endogenous host cells within stem cell niches provide structural support and produce the soluble signals that regulate stem cell function in tissues[1, 28–30] (**Figure 1** inset). An indepth molecular understanding of how MSCs produce the therapeutic benefits demonstrated in numerous clinical trials is critical for the development and design of new clinical trials as well as for the development of newer generations of MSC products that have greater efficacy and sustainability. This chapter will review the current state of knowledge in the use of MSCs as a therapeutic strategy for organ structural and functional repair.
