Abstract

Adipose derived stem cell (ADSC) is the most popular mesenchymal stem cells (MSCs) used in the clinic in recent years. ADSC transplantation has some advantages compared to others from bone marrow, umbilical cord blood... ADSCs produced important growth factors for wound healing, modulate the immune system, decrease inflammation, and home in on injured tissues. Particularly, ADSC extraction from adipose tissue is a simple procedure with minimum invasion in the patients. Therefore, ADSCs were used in the treatment of many diseases and clinical trials since 2000s. To date, ADSC transplantation was approved in some countries to treat medical complications such graft versus host disease, osteoarthritis... This review is an overview of applications and future challenges of ADSC in clinic.

Keywords: Adipose-derived stem cells Stem cells Stem cell transplantation Cytotherapy Regenerative medicine


Introduction

Adipose-derived stem cells (ADSCs) were first identified by Zuk and colleagues at the David Geffen School of Medicine at UCLA in 2001. They termed these cells as processed lipoaspirate cells or “PLA” cells Zuk et al.,2001. Zuk et al. used an enzyme to isolate PLA cells from adipose tissue. PLA cells were also named stromal vascular fraction (SVF) cells that consist of various cell types, including red blood cells, fibroblasts, endothelial cells, smooth muscle cells, pericytes, and preadipocytes Poznanski et al., 1973. However, most of these cell types cannot adhere to the flask surface and are thus eliminated during culture. These adherent cells exhibit stem cell characteristics such as a multilineage differentiation potential Zuk et al., 2001. Subsequently, PLA cells have been isolated by many researchers. PLA cells have been called various names such as ADSCs, adipose-derived adult stem (ADAS) cells, adipose-derived mesenchymal stem cells (AD-MSCs), adipose MSCs (AMSCs), and adipose stromal/stem cells (ASCs).

At the IFAT conference, plastic-adherent cells derived from the SVF were termed ASCs or ADSCs. In recent studies of ADSCs, it has been demonstrated that ADSCs possess the characteristics of MSCs that are isolated from the bone marrow or umbilical cord blood. Therefore, ADSCs are considered as a type of MSC. MSCs were first isolated from the bone marrow by Friedenstein et al. in 1968 Friedenstein et al., 1968. Bone marrow MSCs are considered as the gold standard for MSCs. To unify the classification of MSCs, Dominici et al. (2006) suggested a minimum standard for MSCs. This standard states that MSCs must be plastic adherent when maintained under standard culture conditions; they must express CD105, CD73, and CD90, and lack expression of CD45, CD34, CD14, or CD11b, CD79alpha or CD19, and HLA-DR surface molecules; MSCs must differentiate to osteoblasts, adipocytes, and chondroblasts in vitro Dominici et al.,2006. Although ADSCs satisfy these standards, some authors have argued that ADSCs are different from MSCs.

Studies have shown that adipose tissue is the richest source of MSCs. There are only 0.001-0.01% mononuclear cells in bone marrow Pittenger et al., 1999, while adipose tissue contains up to 10% stem cells in the SVF. Recent studies have documented that 1 g of adipose tissue contains approximately 1-2 x 106 SVF cells, and 10% of these cells are thought to be ADSCs Aust et al., 2004Oedayrajsingh-Varma et al., 2006Zhu et al., 2008. By comparing colony-forming units (CFUs) between umbilical cord blood, bone marrow, liposuctioned fat, and sliced fat, it has been shown that sliced fat contains the most CFUs (28,000 CFUs/g), whereas liposuctioned fat has 3600-10,700 CFUs/g, umbilical cord blood has 200-20,000 CFUs/mL, and bone marrow has 100-1,000 CFUs/mL. Therefore, ADSCs have become a promising candidate for stem cell therapy.

Adsc properties

ADSCs are generally considered as MSCs in the literature. They possess MSC properties, including a fibroblast-like shape when cultured under adherent conditions, differentiation potential for mesenchymal cell lineages such as osteoblasts, chondroblasts, and adipocytes, strong expression of some MSC markers such as CD44, CD73, CD90, and CD105, and negativity for CD14 (monocytes), CD34 (HSCs), CD45 (white blood cells), and HLA-DR (mature cells). However, some studies also show that ADSCs express markers other than those expressed by MSCs ( Table 1 ). ADSCs also express hematopoietic cell markers, pericyte markers, and muscle cell markers. These differences are related to culture conditions and adipose tissue collection. In fact, adipose tissue is usually contaminated with muscular or skin tissue Basu et al., 2011Tallone et al.,2011.

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Table 1.

ADSCs are multipotent stem cells that can differentiate into specific kinds of mesoderm lineage cells, including osteoblasts, chondroblasts, and adipocytes ( Table 2 ). However, many studies also show that ADSCs can transdifferentiate into cell types of other lineages such as the ectoderm or endoderm. Differentiation of ADSCs into specific cells requires specific agents.

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Table 2.

Applications of adipose stem cells in the clinic

Applications of adipose tissue grafts and lipoaspirated fat have been developed for the clinic. Initially, most applications of adipose tissue were related to plastic surgery. Subsequently, some studies used SVFs as concentrated adipose tissue containing mononuclear cells to replace whole adipose tissues. Moreover, transplantation of expanded ADSCs has been applied in the last 5 years.

The use of transplantation of SVFs and ADSCs has rapidly increased as of 2010. Based on gross calculations according to the clinical trials recorded in clinicaltrial.gov and articles cited in PubMed, at least 3000 patients have been treated with ADSCs or SVFs for more than 10 different diseases. Such treatments are related to plastic surgery, digestive diseases, autoimmune diseases, cardiovascular diseases, skeletal regeneration, neurologic diseases, hematological and immunological disorders, diabetes mellitus, urologic disorders and diseases, and lung disorders and diseases ( Figure 1 ). We found 124 clinical trials registered in clinicaltrial.gov with some clinical trials in phase III ( Table 3 ) with a large number of patients (approximately 200 patients). Most clinical trials have been conducted in East Asia, Europe, and North America ( Figure 2 ; Supplement 1 ).

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Figure 1.
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Table 3. Regions with ADSC transplantation in clinical trials
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Figure 2. Map of clinical trials about ADSC transplantation in the world
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Supplement 1.

Studies have shown that ADSC transplantation for the treatment of numerous diseases is safe and effective. To date, there are about 5 clinical trials in Phase III for ADSC transplantation (NCT00475410, NCT01541579, NCT01378390, NCT01803347, andNCT00992147). Four of these clinical trials are related to perianal fistulas treatment. With more than 200 patients, the trial with registration number NCT00475410 showed that perinatal fistula can be effectively treated by ADSC grafts in platelet-rich plasma (PRP) glue with healing rates of approximately 40% at 6months and more than 50% at the 1-year follow-up Herreros et al., 2012. ADSC transplantation has also shown good results for treating many other diseases such as knee osteoarthritis Bui et al., 2014Koh and Choi, 2012, chronic ulcers Marino et al., 2013, Crohn’s fistula Cho et al., 2013de la Portilla et al., 2013Garcia-Olmo et al., 2009Lee et al., 2012, limb ischemia Lee et al.,2012, femoral head necrosis Pak, 2012, Parry-Romberg disease Koh et al., 2012, radiotherapy-induced tissue damage Rigotti et al., 2007, and maxillary and mandibulary bone tissue Kulakov et al., 2008.

Safety of adipose stem cells in the clinic

Similar to any other drug or therapy, ASC transplantation has some limitations and side effects. However, there are different risks for SVFs and ADSCs. SVFs are considered safer than ADSCs. SVFs are directly collected from adipose tissue with enzymes, and the risks of these samples are usually related to adipose tissue processing. In fact, Change et al. (2013) surveyed 100 randomly selected private plastic surgery clinics, 68 plastic surgery departments of general and university hospitals, and 5 biotechnology companies in South Korea that performed ADSC-related procedures using ADSCs they harvested themselves. They found no toxicity resulting from residual collagenase or tumorigenicity associated with the ADSCs Chang et al.,2013.

However, the use of ADSCs or cultured SVF cells to isolate MSCs can be associated with high risks if applied in the clinic. Expanded ADSCs need to be carefully processed and controlled for application to humans. It is considered that cultured ADSCs should be assessed in terms of stability, toxicity, and tumorigenicity during culture. Some recent studies show that the quality of MSCs significantly decreases after long-term culture. Bonab et al. (2006) showed that MSCs derived from bone marrow underwent senescence after 6 passages, as some properties such as population doubling, telomere length, and differentiation potential decrease after the 6th passage Bonab et al., 2006. Furthermore, extended culture of bone marrow-derived MSCs alters their ability to differentiate into hematopoietic progenitor cells without concomitant changes in their phenotype or differentiation capacity Briquet et al., 2010. Another study showed that MSCs can transform into cancer cells Rubio et al., 2005. However, this study was retracted in 2010. In fact, the researchers were unable to reproduce some of the reported spontaneous transformation events and suspected that the phenomenon had occurred because of cross-contamination artifacts de la Fuente et al., 2010Garcia et al., 2010. Rubio et al. also published two studies concerning MSC transformation Rubio et al., 2008aRubio et al., 2008b. However, many other studies show that SVF or ADSC transplantation is safe in animals and humans.

Map of clinical trials about ADSC transplantation in the world. In clinicaltrial.gov, Europe is area with the most clinical trials; and after East Asia, and North America.

In animals, SVF and ADSC transplantation by local injection Gao et al., 2011Gimble et al., 2010Kojima et al., 2011Kondo et al., 2009Van Pham et al., 2013 and intravenous transfusion Lim et al., 2013Sun et al.,2012Tajiri et al., 2014Wang et al., 2013Yanez et al., 2006 has shown high safety. In a recent long-term tumorigenic assessment of a mouse model, MacIsaas et al. injected expanded ADSCs into mice at high doses and the mice were followed up for 1 year MacIsaac et al., 2012. They found no difference in the growth/weight and lifespan of cell- and vehicle-treated animals, and no malignancies were detected in the cell-treated animals. Expanded ADSCs have also been injected into the eyes Rajashekhar et al., 2014. Expanded ADSC transplantation is safe in dogs Black et al., 2008Cui et al., 2007Haghighat et al., 2011Vilar et al., 2013, rabbits Toghraie et al., 2011, rats Tajiri et al., 2014, horses Nicpon et al., 2013Ricco et al., 2013, and pigs Gomez-Mauricio et al., 2013Niada et al., 2013.

In the clinic, most studies of SVF and ADSC transplantation show that local injection and systemic transfusion of ADSCs are safe. Non-expanded SVF cells have been clinically applied to treat multiple sclerosis Riordan et al., 2009, knee osteoarthritis Bui et al., 2014, and femoral head necrosis Namazi,2012Pak, 2012. Autologous expanded ADSCs have been isolated and in vitro-expanded to obtain enough cells for perianal fistula treatment. More than 200 patients were enrolled for intralesional treatment. The results demonstrated that this method is safe and effective de la Portilla et al., 2013Garcia-Olmo et al.,2009Herreros et al., 2012, even after 3 years Guadalajara et al., 2012. The procedure of expanded ADSC-enriched fat grafting has excellent feasibility and safety Kolle et al., 2013. Expanded ADSCs have also been injected into the myocardium to treat chronic myocardial ischemia, which showed safety after 3 years Qayyum et al., 2012.

Lee et al. (2012) showed that intramuscular injection of passage 3 ADSCs into patients with critical limb ischemia is safe, and clinical improvements were observed in 66.7% of patients after 6 months Lee et al.,2012. Koh and Choi injected ADSCs into patients with knee osteoarthritis. They also recorded a clinical improvement without adverse effects Koh and Choi, 2012. Ra et al. (2011) also showed that ADSCs could be expanded up to 12 passages while maintaining their MSC properties. These ADSCs were intravenously transfused into SCID mice, Balb/c-nu mice, and 8 male patients. The results showed that none of the mice or humans developed any serious adverse events related to ADSC transplantation during the 3-month follow-up in humans and over 26 weeks in mice. This study used extremely high doses of 2.5 ˟ 108 cells/kg in mice and 4 ˟ 108 cells in humans Ra et al., 2011b. Ra et al. also used expanded ADSCs for treating autoimmune disease by intravenous transfusion.

They also showed that there were no side effects in the 10 enrolled patients Ra et al., 2011a. Intravenous infusion of autologous expanded ADSCs has been approved as a safe method in the treatment of progressive supranuclear palsy Choi et al., 2014. Intravenous infusion of allogeneic expanded ADSCs is also safe for the treatment of acute respiratory distress syndrome Zheng et al., 2014,

In addition to the risks related to mutations and transformation of ADSC during long-term culture, adverse effects of ADSC transplantation also depend on the culture conditions. In general, GMP-compliant culture is considered to be essential to ensure ADSC quality. One of the concerns of ADSC culture relates to supplementation of fetal bovine serum (FBS) in the culture medium. FBS not only contains xenogeneic proteins that cause immune reactions, but can also transmit viruses. However, some studies have clinically used ADSCs expanded in FBS culture medium.

Svfs and adscs in the clinic

SVFs are a mixture of mononuclear cells including more than 5 kinds of cells, whereas ADSCs are a heterogeneous cell population of the SVF. This cell population is purified by adherent culture. It is easy to understand when there are a comparable mean between adipose tissue and bone marrow, SVFs and mononuclear cells (MNCs). Some studies have considered SVF cells as ADSCs; however, these cells are in reality different. Similar to MNCs and MSCs from bone marrow, there are few studies that have compared transplantation efficiencies between SVFs and ADSCs. Compared with MSCs, MNCs from bone marrow have some advantages in certain cases Karlupia et al., 2014.

Further investigations need to be performed, but it is likely that leukocytes and red blood cells contaminate SVFs or MNCs, resulting in adverse effects. Recent studies in animal models show that MNCs or SVF with leukocyte or red blood cell contamination cause graft-versus-host disease or autoimmune diseases. However, some studies demonstrate that various kinds of stem cells are included in MNCs or SVFs, which contribute to their regeneration Lv et al., 2013.

Future of adsc transplantion

ADSCs have become the main type of adult stem cell that is approved for use in humans. ADSC transplantation has been gradually developed in many countries for the treatment of chronic and degenerative diseases. Although ADSC transplantation has some clinical benefits, the specific mechanisms of ADSC-based treatment are unclear. For successful ADSC application, ADSC migration should be controlled in the human body. Moreover, there should be verification of the in vivo differentiation of ADSCs.

Some recent clinical studies have shown that ADSC transplantation shows better results when used in combination with certain therapies. In fact, a new strategy is the use of adjuvants in ADSC transplantation. Adjuvants are considered as stimulators and differentiating factors that can improve the patient’s condition. The most commonly used adjuvant is PRP. In combination with ADSCs, PRP has been successfully applied in the treatment of osteoarthritis Bui et al., 2014. Furthermore, some cytokines or vitamins may improve the quality or viability of ADSCs in the human body.

For other approaches, studies have focused on the in vitro differentiation of ADSCs into specific cell types. These specific types of cells can be used in stem cell therapy and tissue engineering to create tissues for transplantation.

Abbreviations

AMSCs: Adipose MSCs; Adipose-derived adult stem: ADAS; ADSC: Adipose-derived stem cells; CFUs: colony-forming units; FBS: fetal bovine serum; GMP: Good manufacturing practice; IFAT: International Fat Applied Technology Society; PLA: Lipoaspirate cells; MSC: Mesenchymal stem cell; MNC: Mononuclear cells; PRP: Platelet rich plasma, SVF: stromal vascular fraction

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