**1. Introduction**

Around 1960s, Friedenstein first found that there was a non-hematopoietic stem cell population in the bone marrow that could be differentiated into bone and fibrous tissue [1]; however, this population did not gain broad recognition until Caplan coined the term bone mesenchymal stem cells (MSCs) in 1991 [2]. This umbrella term did raise up the attention of this population, but this term is misleading and very controversial, and many investigators argue against to use this term loosely. As a result, many different terms have been proposed for this or the

© 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.

similar populations, including mesenchymal stromal cells (MSCs), mesenchymal progenitor cells, multipotent mesenchymal stromal cells, bone marrow stromal cells (BMSCs), bone marrow-derived MSCs, multipotent stromal cells, mesenchymal precursor cells, and skeletal stem cells [3]. Currently, most investigators prefer an alternative term, that is, multipotent mesenchymal stromal cells (MSCs). For this reason, we also use this term throughout this chapter.

variety of cytokines and promote angiogenesis. It is reasonable to speculate that MSCs could accelerate fracture healing. In fact, there are experimental evidences to support the idea that MSCs treatment indeed promoted healing of nonunion fractures. For example, MSCs has been transplanted to animals to promote bone loss and fracture healing [11, 12]. Also, there are reports of BMSC treatment of bone nonunion caused by a bone defect, osteogenesis and local microenvironment disorders in patients [13–15]. It was reported that, after traumatic injuries, BMSCs could migrate from blood circulation to the lesion site, and then directly differentiate locally, and replace the injured cells. Consistently, the circulating BMSC can be detected in peripheral blood 39 to 101 hrs after fracture [16]. However, other data also suggested that these circulating cells account for only a small portion of cells in the fracture callus under normal circumstances, suggesting that the majority of the cells at the fracture site are migrated from the adjacent tissues [13]; nevertheless, therapeutic amplification of circulating MSCs through their mobilization could also represent a potential therapeutic opportunity in

Clinical Applications of Mesenchymal Stromal Cells (MSCs) in Orthopedic Diseases

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Indirectly, BMSCs promote bone healing mainly through the secretion of bioactive molecules and extracellular membrane vesicles, which induce angiogenesis, regulate inflammation, inhibit apoptosis, and regulate osteogenesis differentiation. Since defective blood supply (ischemia) is an important cause of nonunion of bone, promoting blood vessel formation is beneficial to the healing of the nonunion bone. MSCs are known to secrete angiogenesisrelated factors include angiopoietin Ang-1 and Ang-2, vascular endothelial growth factor (VEGF), FGF-2, and hepatocyte growth factor (HGF)-1 [17]. Furthermore, BMSCs have an anti-fibrotic effect and can limit that fibrosis progression of fracture zone and promote the regeneration of bone tissue. This is mainly accomplished by immunoregulating, inhibiting TGF-3 mediated differentiation of fibroblasts, inhibiting oxidative stress, and matrix reconstruction [18]. Interestingly, it was also found that HGF, VEGF, and microbubble secreted by BMSCs had an anti-apoptotic effect, which inhibits the apoptosis of transplant cells in the

In addition, other conserved signaling pathways, such as the transformation growth factor

(PDGF), epidermal cell growth factor (EGF), and insulin-like growth factor (IGF), may also indirectly participate in the regulation of BMSCs and promote bone healing processes [21, 22].

Technically, MSCs can be isolated from many different tissues. The iliac crest is the ideal position for bone marrow aspiration. In clinical practice, we indeed found that injection of bone marrow aspirate into the fracture space can promote the healing of fracture and shorten the healing time. For example, in one case with an open tibial fracture, which did not develop callus within the 6 months after surgery, and then we extracted marrow aspirate from the iliac crest and injected it into the fracture space. We found that the fracture healed well 6 months after the transplantation (**Figure 1**). Consistently, bone marrow aspirate injection has been shown to have a potential role in the treatment of aseptic, atrophic nonunions with acceptable alignment and minimal gap, or displacement between fracture fragments [15]. Generally, Tibial nonunion treatment with bone marrow aspirate has been well-documented and found

have been used clinically to enhance and accelerate the bone repair or regeneration.

to be successful in 75–90% of reported tibial nonunion case series [23, 24].

/bone morphogenetic proteins (BMP), Wnt, Hedgehogs, FGF, platelet-derived factor

and its analogs, BMP, BMP-2, and BMP-7,

fracture repair [13].

injured area [19, 20].

Based on these observations, factors such as TGF-β<sup>3</sup>

(TGF)-β<sup>3</sup>

Theoretically, self-renewal without significant loss of their characteristics (stemness) and multi-lineage differentiation potential are the two criteria that define MSCs as real stem cells, but in practice, this heterogeneous population proliferates in vitro as plastic-adherent cells, as fibroblast-like morphology, forms colonies in vitro and can at least differentiate into bone, cartilage and fat cells [4]. In addition, literatures also provided evidence that MSCs can differentiate into multiple other mesenchymal lineages or even non-mesenchymal cell types, including endothelial cells, osteoblasts, chondrocytes, fibroblasts, tenocytes, vascular smooth muscle cells, myoblasts, and neurons [5], though some of these capacities are controversial. The key caveat is that it is unlikely that all cells in the cultural meet the above-mentioned two criteria.

MSC-like cells can be obtained from almost all tissues, including the umbilical cord, amniotic fluid, placenta, adipose tissue, joint synovium, synovial fluid, dental pulp, endosteum, and periosteum [6]. Cultured MSCs have been characterized either by using cell surface antigens and/or by examining the cells' differentiation potential. The International Society for Cellular Therapy recommended that cells should fulfill the following criteria to be considered as MSCs: (1) the cells must be plastic adherent when maintained under standard culture conditions; (2) they must express CD73, CD90, and CD105 markers and should not express CD34, CD45, CD14, HLA-DR, CD11b, or CD19; and (3) they should be able to differentiate at least into osteoblasts, chondroblasts, and adipocytes in vitro [7]; however, this criteria has obvious problems therefore not been commonly accepted. For this reason, it is still challenging to consistently isolate or purify a well-defined clinical applicable MSC population.

On the other hand, the increasingly aging population has made the degenerative, non-traumatic and traumatic musculoskeletal diseases main socioeconomic issues, and MSCs seem to be a promising solution. In fact, MSCs have been widely used as a treatment for numerous orthopedic diseases, including bone defects, osteoarthritis (OA), femoral head necrosis, degenerative disc, spinal cord injury, knee varus, osteogenesis imperfecta, and other systemic bone diseases [8]. Currently, orthopedic researchers are still focusing on overcoming a variety of challenges so that they can fully realize the clinical therapeutic potential of MSCs, and the long-term goal is to change the main treatment strategy in the field of orthopedics from surgical replacement and reconstruction to bioregeneration and prevention [9].

In this chapter, we will briefly update the main advancements in these areas and discuss the major current and potential future applications pathways.
