Abstract
Adipose-derived stem cells (ADSCs) are the most commonly used type of mesenchymal stem cell (MSC) in the clinic. ADSCs have some advantages in transplantation compared with MSCs from bone marrow and umbilical cord blood. ADSCs produce important growth factors for wound healing, modulate the immune system, decrease inflammation, and home to injured tissues. In particular, ADSC extraction from adipose tissue is a simple procedure with minimum invasiveness. Therefore, ADSCs have been evaluated in clinical trials and used in the treatment of many diseases. To date, ADSC transplantation has been approved in some countries to treat medical complications such as perianal pistula and osteoarthritis. This review provides an overview of the applications and future challenges of the use of ADSCs in clinical settings.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
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., 2004; Oedayrajsingh-Varma et al., 2006; Zhu 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., 2011; Tallone et al., 2011).
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.
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 (Fig. 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 (Fig. 2 ; 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., 2014; Koh and Choi, 2012), chronic ulcers (Marino et al., 2013), Crohn’s fistula (Cho et al., 2013; de la Portilla et al., 2013; Garcia-Olmo et al., 2009; Lee 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., 2010; Garcia et al., 2010). Rubio et al. also published two studies concerning MSC transformation (Rubio et al., 2008a; Rubio et al., 2008b). However, many other studies show that SVF or ADSC transplantation is safe in animals and humans.
In animals, SVF and ADSC transplantation by local injection (Gao et al., 2011; Gimble et al., 2010; Kojima et al., 2011; Kondo et al., 2009; Van Pham et al., 2013) and intravenous transfusion (Lim et al., 2013; Sun et al., 2012; Tajiri et al., 2014; Wang et al., 2013; Yanez 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., 2008; Cui et al., 2007; Haghighat et al., 2011; Vilar et al., 2013), rabbits (Toghraie et al., 2011), rats (Tajiri et al., 2014), horses (Nicpon et al., 2013; Ricco et al., 2013), and pigs (Gomez-Mauricio et al., 2013; Niada 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, 2012; Pak, 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., 2013; Garcia-Olmo et al., 2009; Herreros 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.
Acknowledgment
This study was funded by Ministry of Science and Technology, Vietnam under grant DTDL.2012-G/23.
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
Competing interests
The authors declare that they have no competing interests.
Open Access
This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
References
Aust, L., Devlin, B., Foster, S.J., Halvorsen, Y.D., Hicok, K., du Laney, T., Sen, A., Willingmyre, G.D., and Gimble, J.M. (2004). Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 6, 7–14.
Basu, J., Genheimer, C.W., Guthrie, K.I., Sangha, N., Quinlan, S.F., Bruce, A.T., Reavis, B., Halberstadt, C., Ilagan, R.M., and Ludlow, J.W. (2011). Expansion of the human adipose-derived stromal vascular cell fraction yields a population of smooth muscle-like cells cells in the clinicwith markedly distinct phenotypic and functional properties relative to mesenchymal stem cells. Tissue engineering Part C, Methods 17, 843–860.
Behr, B., Tang, C., Germann, G., Longaker, M.T., and Quarto, N. (2011). Locally applied vascular endothelial growth factor A increases the osteogenic healing capacity of human adipose-derived stem cells by promoting osteogenic and endothelial differentiation. Stem cells (Dayton, Ohio) 29, 286–296.
Black, L.L., Gaynor, J., Adams, C., Dhupa, S., Sams, A.E., Taylor, R., Harman, S., Gingerich, D.A., and Harman, R. (2008). Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Veterinary therapeutics: research in applied veterinary medicine 9, 192–200.
Bonab, M.M., Alimoghaddam, K., Talebian, F., Ghaffari, S.H., Ghavamzadeh, A., and Nikbin, B. (2006). Aging of mesenchymal stem cell in vitro. BMC cell biology 7, 14.
Briquet, A., Dubois, S., Bekaert, S., Dolhet, M., Beguin, Y., and Gothot, A. (2010). Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID-repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages. Haematologica 95, 47–56.
Bui, K.H.-T., Duong, T.D., Nguyen, N.T., Nguyen, T.D., Le, V.T., Mai, V.T., Phan, N.L.-C., Le, D.M., Phan, N.K., and Pham, P.V. (2014). Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet-rich plasma: a clinical study. 2014 1.
Chang, H., Do, B.R., Che, J.H., Kang, B.C., Kim, J.H., Kwon, E., Kim, J.Y., and Min, K.H. (2013). Safety of adipose-derived stem cells and collagenase in fat tissue preparation. Aesthetic plastic surgery 37, 802–808.
Chen, L., Lu, X., Li, S., Sun, Q., Li, W., and Song, D. (2012). Sustained delivery of BMP-2 and platelet-rich plasma-released growth factors contributes to osteogenesis of human adipose- derived stem cells. Orthopedics 35, e1402–1409.
Cho, Y.B., Lee, W.Y., Park, K.J., Kim, M., Yoo, H.W., and Yu, C.S. (2013). Autologous adipose tissue-derived stem cells for the treatment of Crohn’s fistula: a phase I clinical study. Cell transplantation 22, 279–285.
Choi, S.W., Park, K.B., Woo, S.K., Kang, S.K., and Ra, J.C. (2014). Treatment of progressive supranuclear palsy with autologous adipose tissue-derived mesenchymal stem cells: a case report. Journal of medical case reports 8, 87.
Cui, L., Liu, B., Liu, G., Zhang, W., Cen, L., Sun, J., Yin, S., Liu, W., and Cao, Y. (2007). Repair of cranial bone defects with adipose derived stem cells and coral scaffold in a canine model. Biomaterials 28, 5477–5486.
de la Fuente, R., Bernad, A., Garcia-Castro, J., Martin, M.C., and Cigudosa, J.C. (2010). Retraction: Spontaneous human adult stem cell transformation. Cancer research 70, 6682.
de la Portilla, F., Alba, F., Garcia-Olmo, D., Herrerias, J.M., Gonzalez, F.X., and Galindo, A. (2013). Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. International journal of colorectal disease 28, 313-323.
Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, Krause, D., Deans, R., Keating, A., Prockop, D., and Horwitz, E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317.
Eom, Y.W., Lee, J.E., Yang, M.S., Jang, I.K., Kim, H.E., Lee, D.H., Kim, Y.J., Park, W.J., Kong, J.H., Shim, K.Y., et al. (2011). Rapid isolation of adipose tissue-derived stem cells by the storage of lipoaspirates. Yonsei medical journal 52, 999–1007.
Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., and Frolova, G.P. (1968). Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6, 230247.
Gao, W., Qiao, X., Ma, S., and Cui, L. (2011). Adipose-derived stem cells accelerate neovascularization in ischaemic diabetic skin flap via expression of hypoxia-inducible factor-1alpha. Journal of cellular and molecular medicine 15, 2575–2585.
Garcia, S., Bernad, A., Martin, M.C., Cigudosa, J.C., Garcia-Castro, J., and de la Fuente, R. (2010). Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells. Experimental cell research 316, 1648–1650.
Garcia-Olmo, D., Herreros, D., Pascual, I., Pascual, J.A., Del-Valle, E., Zorrilla, J., De-La-Quintana, P., Garcia-Arranz, M., and Pascual, M. (2009). Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Diseases of the colon and rectum 52, 79–86.
Gharibi, B., and Hughes, F.J. (2012). Effects of medium supplements on proliferation, differentiation potential, and in vitro expansion of mesenchymal stem cells. Stem cells translational medicine 1, 771782.
Gimble, J.M., Guilak, F., and Bunnell, B.A. (2010). Clinical and preclinical translation of cell-based therapies using adipose tissue- derived cells. Stem cell research & therapy 1, 19.
Gomez-Mauricio, R.G., Acarregui, A., Sanchez-Margallo, F.M., Crisostomo, V., Gallo, I., Hernandez, R.M., Pedraz, J.L., Orive, G., and Martin-Cancho, M.F. (2013). A preliminary approach to the repair of myocardial infarction using adipose tissue-derived stem cells encapsulated in magnetic resonance-labelled alginate microspheres in a porcine model. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV 84, 29–39.
Gronthos, S., Franklin, D.M., Leddy, H.A., Robey, P.G., Storms, R.W., and Gimble, J.M. (2001). Surface protein characterization of human adipose tissue-derived stromal cells. Journal of cellular physiology 189, 54–63.
Guadalajara, H., Herreros, D., De-La-Quintana, P., Trebol, J., Garcia-Arranz, M., and Garcia-Olmo, D. (2012). Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. International journal of colorectal disease 27, 595–600.
Haghighat, A., Akhavan, A., Hashemi-Beni, B., Deihimi, P., Yadegari, A., and Heidari, F. (2011). Adipose derived stem cells for treatment of mandibular bone defects: An autologous study in dogs. Dental research journal 8, S51–57.
Haimi, S., Suuriniemi, N., Haaparanta, A.M., Ella, V., Lindroos, B., Huhtala, H., Raty, S., Kuokkanen, H., Sandor, G.K., Kellomaki, M., et al. (2009). Growth and osteogenic differentiation of adipose stem cells on PLA/bioactive glass and PLA/beta-TCP scaffolds. Tissue engineering Part A 15, 1473–1480.
Hao, W., Hu, Y.Y., Wei, Y.Y., Pang, L., Lv, R., Bai, J.P., Xiong, Z., and Jiang, M. (2008). Collagen I gel can facilitate homogenous bone formation of adipose-derived stem cells in PLGA-beta-TCP scaffold. Cells, tissues, organs 187, 89–102.
Herreros, M.D., Garcia-Arranz, M., Guadalajara, H., De-La- Quintana, P., and Garcia-Olmo, D. (2012). Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Diseases of the colon and rectum 55, 762–772.
Hong, L., Colpan, A., Peptan, I.A., Daw, J., George, A., and Evans, C.A. (2007). 17-Beta estradiol enhances osteogenic and adipogenic differentiation of human adipose-derived stromal cells. Tissue engineering 13, 1197–1203.
Jin, X., Sun, Y., Zhang, K., Wang, J., Shi, T., Ju, X., and Lou, S. (2007). Ectopic neocartilage formation from predifferentiated human adipose derived stem cells induced by adenoviral-mediated transfer of hTGF beta2. Biomaterials 28, 2994–3003.
Karlupia, N., Manley, N.C., Prasad, K., Schafer, R., and Steinberg, G.K. (2014). Intra-arterial transplantation of human umbilical cord blood mononuclear cells is more efficacious and safer compared with umbilical cord mesenchymal stromal cells in a rodent stroke model. Stem cell research & therapy 5, 45.
Katz, A.J., Tholpady, A., Tholpady, S.S., Shang, H., and Ogle, R.C. (2005). Cell surface and transcriptional characterization of human adipose-derived adherent stromal (hADAS) cells. Stem cells (Dayton, Ohio) 23, 412–423.
Koh, K.S., Oh, T.S., Kim, H., Chung, I.W., Lee, K.W., Lee, H.B., Park, E.J., Jung, J.S., Shin, I.S., Ra, J.C., et al. (2012). Clinical application of human adipose tissue-derived mesenchymal stem cells in progressive hemifacial atrophy (Parry-Romberg disease) with microfat grafting techniques using 3-dimensional computed tomography and 3-dimensional camera. Annals of plastic surgery 69, 331–337.
Koh, Y.G., and Choi, Y.J. (2012). Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. The Knee 19, 902–907.
Kojima, T., Kanemaru, S., Hirano, S., Tateya, I., Ohno, S., Nakamura, T., and Ito, J. (2011). Regeneration of radiation damaged salivary glands with adipose-derived stromal cells. The Laryngoscope 121, 1864–1869.
Kolle, S.F., Fischer-Nielsen, A., Mathiasen, A.B., Elberg, J.J., Oliveri, R.S., Glovinski, P.V., Kastrup, J., Kirchhoff, M., Rasmussen, B.S., Talman, M.L et al. (2013). Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial. Lancet 382, 11131120.
Kondo, K., Shintani, S., Shibata, R., Murakami, H., Murakami, R., Imaizumi, M., Kitagawa, Y., and Murohara, T. (2009). Implantation of adipose-derived regenerative cells enhances ischemia-induced angiogenesis. Arteriosclerosis, thrombosis, and vascular biology 29, 61–66.
Kulakov, A.A., Goldshtein, D.V., Grigoryan, A.S., Rzhaninova, A.A., Alekseeva, I.S., Arutyunyan, I.V., and Volkov, A.V. (2008). Clinical study of the efficiency of combined cell transplant on the basis of multipotent mesenchymal stromal adipose tissue cells in patients with pronounced deficit of the maxillary and mandibulary bone tissue. Bulletin of experimental biology and medicine 146, 522–525.
Lee, H.C., An, S.G., Lee, H.W., Park, J.S., Cha, K.S., Hong, T.J., Park, J.H., Lee, S.Y., Kim, S.P., Kim, Y.D., et al. (2012). Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circulation journal: official journal of the Japanese Circulation Society 76, 1750–1760.
Leong, D.T., Khor, W.M., Chew, F.T., Lim, T.C., and Hutmacher, D.W. (2006). Characterization of osteogenically induced adipose tissue-derived precursor cells in 2-dimensional and 3-dimensional environments. Cells, tissues, organs 182, 1–11.
Lim, J.Y., Ra, J.C., Shin, I.S., Jang, Y.H., An, H.Y., Choi, J.S., Kim, W.C., and Kim, Y.M. (2013). Systemic transplantation of human adipose tissue-derived mesenchymal stem cells for the regeneration of irradiation-induced salivary gland damage. PloS one 8, e71167.
Lin, G., Garcia, M., Ning, H., Banie, L., Guo, Y.L., Lue, T.F., and Lin, C.S. (2008). Defining stem and progenitor cells within adipose tissue. Stem cells and development 17, 1053–1063.
Lu, C.H., Lin, K.J., Chiu, H.Y., Chen, C.Y., Yen, T.C., Hwang, S.M., Chang, Y.H., and Hu, Y.C. (2012). Improved chondrogenesis and engineered cartilage formation from TGF-beta3-expressing adipose- derived stem cells cultured in the rotating-shaft bioreactor. Tissue engineering Part A 18, 2114–2124.
Lv, Y.T., Zhang, Y., Liu, M., Qiuwaxi, J.N., Ashwood, P., Cho, S.C., Huan, Y., Ge, R.C., Chen, X.W., Wang, Z.J et al. (2013). Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Journal of translational medicine 11, 196.
MacIsaac, Z.M., Shang, H., Agrawal, H., Yang, N., Parker, A., and Katz, A.J. (2012). Long-term in-vivo tumorigenic assessment of human culture-expanded adipose stromal/stem cells. Experimental cell research 318, 416–423.
Marino, G., Moraci, M., Armenia, E., Orabona, C., Sergio, R., De Sena, G., Capuozzo, V., Barbarisi, M., Rosso, F., Giordano, G., et al. (2013). Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. The Journal of surgical research 185, 3644.
Marino, G., Rosso, F., Cafiero, G., Tortora, C., Moraci, M., Barbarisi, M., and Barbarisi, A. (2010). Beta-tricalcium phosphate 3D scaffold promote alone osteogenic differentiation of human adipose stem cells: in vitro study. Journal of materials science Materials in medicine 21, 353–363.
Mitchell, J.B., McIntosh, K., Zvonic, S., Garrett, S., Floyd, Z.E., Kloster, A., Di Halvorsen, Y., Storms, R.W., Goh, B., Kilroy, G., et al. (2006). Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem cells (Dayton, Ohio) 24, 376–385.
Namazi, H. (2012). Autologous adipose tissue-derived stem cells induce persistent bone-like tissue in osteonecrotic femoral heads: a molecular mechanism. Pain physician 15, E345; author reply E345.
Niada, S., Ferreira, L.M., Arrigoni, E., Addis, A., Campagnol, M., Broccaioli, E., and Brini, A.T. (2013). Porcine adipose-derived stem cells from buccal fat pad and subcutaneous adipose tissue for future preclinical studies in oral surgery. Stem cell research & therapy 4, 148.
Nicpon, J., Marycz, K., and Grzesiak, J. (2013). Therapeutic effect of adipose-derived mesenchymal stem cell injection in horses suffering from bone spavin. Polish journal of veterinary sciences 16, 753–754.
Oedayrajsingh-Varma, M.J., van Ham, S.M., Knippenberg, M., Helder, M.N., Klein-Nulend, J., Schouten, T.E., Ritt, M.J., and van Milligen, F.J. (2006). Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissueharvesting procedure. Cytotherapy 8, 166–177.
Pak, J. (2012). Autologous adipose tissue-derived stem cells induce persistent bone-like tissue in osteonecrotic femoral heads. Pain physician 15, 75–85.
Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S., and Marshak, D.R. (1999). Multilineage potential of adult human mesenchymal stem cells. Science (New York, NY) 284, 143–147.
Poznanski, W.J., Waheed, I., and Van, R. (1973). Human fat cell precursors. Morphologic and metabolic differentiation in culture. Laboratory investigation; a journal of technical methods and pathology 29, 570–576.
Qayyum, A.A., Haack-Sorensen, M., Mathiasen, A.B., Jorgensen, E., Ekblond, A., and Kastrup, J. (2012). Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regenerative medicine 7, 421–428.
Ra, J.C., Kang, S.K., Shin, I.S., Park, H.G., Joo, S.A., Kim, J.G., Kang, B.C., Lee, Y.S., Nakama, K., Piao, M., et al. (2011a). Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. Journal of translational medicine 9, 181.
Ra, J.C., Shin, I.S., Kim, S.H., Kang, S.K., Kang, B.C., Lee, H.Y., Kim, Y.J., Jo, J.Y., Yoon, E.J., Choi, H.J et al. (2011b). Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem cells and development 20, 1297–1308.
Rajashekhar, G., Ramadan, A., Abburi, C., Callaghan, B., Traktuev, D.O., Evans-Molina, C., Maturi, R., Harris, A., Kern, T.S., and March, K.L. (2014). Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy. PloS one 9, e84671.
Ricco, S., Renzi, S., Del Bue, M., Conti, V., Merli, E., Ramoni, R., Lucarelli, E., Gnudi, G., Ferrari, M., and Grolli, S. (2013). Allogeneic adipose tissue-derived mesenchymal stem cells in combination with platelet rich plasma are safe and effective in the therapy of superficial digital flexor tendonitis in the horse. International journal of immunopathology and pharmacology 26, 61–68.
Rigotti, G., Marchi, A., Galie, M., Baroni, G., Benati, D., Krampera, M., Pasini, A., and Sbarbati, A. (2007). Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plastic and reconstructive surgery 119, 1409-1422; discussion 1423–1404.
Riordan, N.H., Ichim, T.E., Min, W.P., Wang, H., Solano, F., Lara, F., Alfaro, M., Rodriguez, J.P., Harman, R.J., Patel, A.N et al. (2009). Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. Journal of translational medicine 7, 29.
Rubio, D., Garcia, S., De la Cueva, T., Paz, M.F., Lloyd, A.C., Bernad, A., and Garcia-Castro, J. (2008a). Human mesenchymal stem cell transformation is associated with a mesenchymal-epithelial transition. Experimental cell research 314, 691–698.
Rubio, D., Garcia, S., Paz, M.F., De la Cueva, T., Lopez-Fernandez, L.A., Lloyd, A.C., Garcia-Castro, J., and Bernad, A. (2008b). Molecular characterization of spontaneous mesenchymal stem cell transformation. PloS one 3, e1398.
Rubio, D., Garcia-Castro, J., Martin, M.C., de la Fuente, R., Cigudosa, J.C., Lloyd, A.C., and Bernad, A. (2005). Spontaneous human adult stem cell transformation. Cancer research 65, 3035-3039.
Schiller, Z.A., Schiele, N.R., Sims, J.K., Lee, K., and Kuo, C.K. (2013). Adipogenesis of adipose-derived stem cells may be regulated via the cytoskeleton at physiological oxygen levels in vitro. Stem cell research & therapy 4, 79.
Song, I., Kim, B.S., Kim, C.S., and Im, G.I. (2011). Effects of BMP-2 and vitamin D3 on the osteogenic differentiation of adipose stem cells. Biochemical and biophysical research communications 408, 126–131.
Sun, C.K., Chang, C.L., Lin, Y.C., Kao, Y.H., Chang, L.T., Yen, C.H., Shao, P.L., Chen, C.H., Leu, S., and Yip, H.K. (2012). Systemic administration of autologous adipose-derived mesenchymal stem cells alleviates hepatic ischemia-reperfusion injury in rats. Critical care medicine 40, 1279–1290.
Tajiri, N., Acosta, S.A., Shahaduzzaman, M., Ishikawa, H., Shinozuka, K., Pabon, M., Hernandez-Ontiveros, D., Kim, D.W., Metcalf, C., Staples, Mv et al. (2014). Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 313–326.
Tallone, T., Realini, C., Bohmler, A., Kornfeld, C., Vassalli, G., Moccetti, T., Bardelli, S., and Soldati, G. (2011). Adult human adipose tissue contains several types of multipotent cells. Journal of cardiovascular translational research 4, 200–210.
Toghraie, F.S., Chenari, N., Gholipour, M.A., Faghih, Z., Torabinejad, S., Dehghani, S., and Ghaderi, A. (2011). Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in Rabbit. The Knee 18, 71–75.
Traktuev, D.O., Merfeld-Clauss, S., Li, J., Kolonin, M., Arap, W., Pasqualini, R., Johnstone, B.H., and March, K.L. (2008). A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circulation research 102, 77–85.
Van Pham, P., Bui, K.H., Ngo, D.Q., Vu, N.B., Truong, N.H., Phan, N.L., Le, D.M., Duong, T.D., Nguyen, T.D., Le, V.T., et al. (2013). Activated platelet-rich plasma improves adipose-derived stem cell transplantation efficiency in injured articular cartilage. Stem cell research & therapy 4, 91.
Varma, M.J., Breuls, R.G., Schouten, T.E., Jurgens, W.J., Bontkes, J., Schuurhuis, G.J., van Ham, S.M., and van Milligen, F.J. (2007). Phenotypical and functional characterization of freshly isolated adipose tissue-derived stem cells. Stem cells and development 16, 91–104.
Vilar, J.M., Morales, M., Santana, A., Spinella, G., Rubio, M., Cuervo, B., Cugat, R., and Carrillo, J.M. (2013). Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC veterinary research 9, 131.
Wang, Y.L., Li, G., Zou, X.F., Chen, X.B., Liu, T., and Shen, Z.Y. (2013). Effect of autologous adipose-derived stem cells in renal cold ischemia and reperfusion injury. Transplantation proceedings 45, 3198–3202.
Yanez, R., Lamana, M.L., Garcia-Castro, J., Colmenero, I., Ramirez, M., and Bueren, J.A. (2006). Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem cells (Dayton, Ohio) 24, 2582–2591.
Yoshimura, K., Shigeura, T., Matsumoto, D., Sato, T., Takaki, Y., Aiba-Kojima, E., Sato, K., Inoue, K., Nagase, T., Koshima, I., et al. (2006). Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. Journal of cellular physiology 208, 64–76.
Zannettino, A.C., Paton, S., Arthur, A., Khor, F., Itescu, S., Gimble, J.M., and Gronthos, S. (2008). Multipotential human adipose- derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. Journal of cellular physiology 214, 413–421.
Zeng, G., Lai, K., Li, J., Zou, Y., Huang, H., Liang, J., Tang, X., Wei, J., and Zhang, P. (2013). A rapid and efficient method for primary culture of human adipose-derived stem cells. Organogenesis 9, 287–295.
Zheng, G., Huang, L., Tong, H., Shu, Q., Hu, Y., Ge, M., Deng, K., Zhang, L., Zou, B., Cheng, B., et al. (2014). Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respiratory research 15, 39.
Zhu, Y., Liu, T., Song, K., Fan, X., Ma, X., and Cui, Z. (2008). Adipose-derived stem cell: a better stem cell than BMSC. Cell biochemistry and function 26, 664–675.
Zimmerlin, L., Donnenberg, V.S., Pfeifer, M.E., Meyer, E.M., Peault, B., Rubin, J.P., and Donnenberg, A.D. (2010). Stromal vascular progenitors in adult human adipose tissue. Cytometry Part A: the journal of the International Society for Analytical Cytology 77, 2230.
Zuk, P.A., Zhu, M., Ashjian, P., De Ugarte, D.A., Huang, J.I., Mizuno, H., Alfonso, Z.C., Fraser, J.K., Benhaim, P., and Hedrick, M.H. (2002). Human adipose tissue is a source of multipotent stem cells. Molecular biology of the cell 13, 4279–4295.
Zuk, P.A., Zhu, M., Mizuno, H., Huang, J., Futrell, J.W., Katz, A.J., Benhaim, P., Lorenz, H.P., and Hedrick, M.H. (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering 7, 211–228.
Pham, P. (2014). Adipose stem cells in the clinic. Biomedical Research And Therapy, 1(2):57-70
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Van Pham, P. Adipose stem cells in the clinic. Biomed Res Ther 1, 11 (2014). https://doi.org/10.7603/s40730-014-0011-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.7603/s40730-014-0011-8