Abstract: Adipose tissue is an abundant source of mesenchymal stem cells, which have shown promise in the field of regenerative medicine. Furthermore, these cells can be readily harvested in large numbers with low donor-site morbidity. During the past decade, numerous studies have provided preclinical data on the safety and efficacy of adipose-derived stem cells, supporting the use of these cells in future clinical applications. Various clinical trials have shown the regenerative capability of adipose-derived stem cells in subspecialties of medical fields such as plastic surgery, orthopedic surgery, oral and maxillofacial surgery, and cardiac surgery. In addition, a great deal of knowledge concerning the harvesting, characterization, and culture of adipose-derived stem cells has been reported. This review will summarize data from in vitro studies, pre-clinical animal models, and recent clinical trials concerning the use of adipose-derived stem cells in regenerative medicine.

Introduction

In the field of regenerative medicine, basic research and preclinical studies have been conducted to overcome clinical shortcomings with the use of mesenchymal stem cells (MSCs). MSCs are present in adult tissues, including bone marrow and adipose tissue. For many years, bone marrow-derived stem cells (BSCs) were the primary source of stem cells for tissue engineering applications (Caplan, 1991; Pittenger et al., 1999; Caplan, 2007). However, recent studies have shown that subcutaneous adipose tissue provides a clear advantage over other stem cell sources due to the ease with which adipose tissue can be accessed as well as the ease of isolating stem cells from harvested tissue (Schffler et al., 2007). Initial enzymatic digestion of adipose tissue yields a mixture of stromal and vascular cells referred to as the stromal-vascular fraction (SVF) (Traktuev et al., 2008). A putative stem cell population within this SVF was first identified by Zuk et al. and named processed lipoaspirate (PLA) cells (Zuk et al., 2001; Zuk et al., 2002).

There is no consensus when it comes to the nomenclature used to describe progenitor cells from adipose tissue-derived stroma, which can sometimes lead to confusion. The term PLA refers to adipose-derived stromal cells and adipose-derived stem cells (ASCs) and describes cells obtained immediately after collagenase digestion. Accordingly, the term ASC will be used throughout this review.

ASCs exhibit stable growth and proliferation kinetics and can differentiate toward osteogenic, chondrogenic, adipogenic, myogenic, or neurogenic lineages in vitro (Zuk et al., 2002; Izadpanah et al., 2006; Romanov et al., 2005). Furthermore, a group has recently described the isolation and culture of ASCs with multipotent differentiation capacity at the single-cell level (Rodriguez, et al., 2005).

Using these attractive cell populations, recent studies have explored the safety and efficacy of implanted/administrated ASCs in various animal models. Furthermore, clinical trials using ASCs have been initiated in some medical subspecialties. This review summarizes the current preclinical data and ongoing clinical trials and their outcomes in a variety of medical fields.

Characterization and Localization

ASCs express the mesenchymal stem cell markers CD10, CD13, CD29, CD34, CD44, CD54, CD71, CD90, CD105, CD106, CD117, and STRO-1. They are negative for the hematopoietic lineage markers CD45, CD14, CD16, CD56, CD61, CD62E, CD104, and CD106 and for the endothelial cell (EC) markers CD31, CD144, and von Willebrand factor (Zuk et al., 2002; Musina et al., 2005; Romanov et al., 2005). Morphologically, they are fibroblast-like and preserve their shape after expansion in vitro (Zuk et al., 2002; Arrigoni et al., 2009; Zannettino et al., 2008).

The similarities between ASCs and BSCs may indicate that ASCs are derived from circulating BSCs, which infiltrate into the adipose compartment through vessel walls (Zuk et al., 2002; Zannettino et al., 2008; Brighton et al., 1992; Canfield et al., 2000; Bianco et al., 2001). On the other hand, according to a recent theory, these stem cells are actually pericytes (Traktuev et al., 2008; Chen et al., 2009; Crisan et al., 2008; Zannettino et al., 2008; Tintut et al., 2003; Abedin et al., 2004; Amos et al., 2008). Pericytes around microvessels express alpha-smooth muscle actin (-SMA) as well as certain MSC markers (CD44, CD73, CD90, CD105); however, they do not express endothelial or hematopoietic cell markers (Chen et al., 2009). Pericytes adhere, proliferate in culture, sustain their initial antigenic profile, and can differentiate into bone, cartilage and fat cells (Chen et al., 2009). Moreover, injected MSCs migrate to the blood vessels in vivo and become pericytes (Chen et al., 2009). Considering the above-mentioned data, it can be speculated that pericytes are the ancestors of MSCs, but this does not mean that all MSCs are descendants of pericytes (Chen et al., 2009) or that all pericytes are necessarily stem cells (Lin et al., 2008; Traktuev et al., 2008; da Silva et al., 2008; Abedin et al., 2004; Tintut et al., 2003; Zannettino et al., 2008; Amos et al., 2008).

Traktuev et al. (2008) defined a periendothelial pericyte-like subpopulation of ASCs. These cells were CD34+, CD31-, CD45-, and CD144- and expressed mesenchymal cell markers, smooth muscle antigens, and pericytic markers, including chondroitin sulfate proteoglycan (NG2), CD140a, and CD140b (PDGF receptor and , respectively) (Traktuev et al., 2008; Amos et al., 2008). However, Lin et al. (2008) could not co-localize CD34 and CD104b, and thus concluded that CD34+/CD31- cells of adipose vasculature are not pericytes.

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Adipose-derived Stem Cells: Current Findings and Future ...