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1 Biomaterials Research (2009) 13(3) : <Review> Biomaterials Research C The Korean Society for Biomaterials 지방줄기세포를이용한조직재생의현황 Updates on the Tissue Regeneration Using Adipose Stem Cells 임군일 Gun-Il Im 동국대학교일산병원정형외과 Dept. of Orthopaedics, Dongguk University International Hospital (Received February 20, 2009/Acccepted March 27, 2009) Adipose tissue provides abundant source of adult stem cells. Adipose stem cells were proven to differentiate into various musculoskeletal tissue. Their easy availability and minimal morbidity associated with procurement provoked a greate interest in the field of tissue engineering, and there has been exponetial increase in the number of publications on this subject in recent years. The adipose stem cells have different characteristics depending on the location the are harvested. They are most commonly isolated from lipoaspirates from plastic surgery. Their manifestations of surface phenotypes are similar but not totally identical to mesenchymal stem cell from bone marrow (BMMSCS), and conditions different from BMMSCs are needed for osteogenic or chondrogenic differentiations. In this review article, recent updates on the isolation method, characterization, capacity for differentiation, immune response as well as application to bone and cartilage tissue engineering are introduced. Key Words: Adipose stem cell, tissue engineering, differentiation 조 서 직공학과재생의학에있어서핵심은세포원을확보하고그세포를증식시켜원하는조직으로분화시키는것이다. 최근인체배아줄기세포의전분화능을확인함에따라많은기대가모아졌으나현재까지분화를통제할수있는방법에대하여잘모르는상태이며더구나배아줄기세포의연구에있어서는윤리적, 법률적인문제가뒤따르는실정이다. 1,2) 이러한상황에서연구자들은대안이되는세포원인성체줄기세포에관심을가지기시작하였다. 이들은개체내에존재하면서일생동안자기복제와필요한경우각조직에서필요한세포로분화하는역할을한다. 3,4) 현재여러조직에서성체줄기세포를발견하였으나골수가가장대표적으로연구되었으며치료목적으로도가장많이쓰이고있다. 5-8) 그러나골수의양은제한되어있고줄기세포의수는연령의증가에따라감소하며이렇게증식시킨골수세포를분화시킬경우골분화능력도감소하는것으로알려져있다. 조직공학적으로골을만드는데높은세포농도가필요하다고알려져있으므로다량의세포를공여부에손상을주지않고획득할수있는세포원이필요하다. 현재그러한조건을가장충족시킬수있는것은지방줄기세포로서체내에가장많이존 * 책임연락저자 : gunil@duih.org 론 재한다. 지방줄기세포는골수줄기세포와비슷한섬유모세포모양의형태를가지며핵과소포체가잘발달되어있다. 3) 본고에서는지방줄기세포이론의역사와그분리와동정법, 분화법및임상적이용에대하여소개하고자한다. 지방줄기세포의역사 Zuk 등이지방조직에서줄기세포의존재를최초로보고하였는데 2편의논문에서이줄기세포들의분화능력과줄기세포표지단백질이발현됨을증명하였다. 1,2) 그러나그전연구에서도지방전구세포의골형성능력에대해서는증명이되어있었다. 9-11) Zuk 등의연구후에여러그룹에서지방줄기세포의분화능이입증되었고여러표지자의존재를증명하였다. 현재사람외에도쥐, 토끼, 개, 돼지등여러동물에서지방줄기세포의존재와골, 연골, 근육, 신경모세포로의분화가증명되어있다 ) 지방줄기세포의명명은 adipose stem cell (ASC), adipose-derived adult stem cell (ADAS), adipose-derived stem cell (ADSCs), adipose mesenchymal stem cell (AdMSC) 이쓰여왔고저자는 adipose tissue-derived mesenchymal stem cell (ATMSC) 라는용어를사용하여여러논문에발표하였지만 22-24) 2004년피츠버그에서열린국제지방응용기술학회 (International Fat Applied Technology Society) 에서 adipose stem cell (ASC) 라는용어를채택하여현재권장되고있다. 77

2 78 임군일 지방조직에따른줄기세포의특성 지방에는백색지방과갈색지방이있는데같은백색지방이라하더라도한군데에서채취된지방줄기세포는다른데에서나온세포에비하여다른특성을가지고있을수있다. 25) 백색지방에서발견되는성체줄기세포는갈색지방에서발견되는세포에비하여수가많으며빨리자라고골모세포로의분화도잘된다. 26) 또한피하지방에서분리된지방줄기세포가복강내지방에분리된세포에비하여증식은잘되나골로의분화능력은떨어지며 12,26) 슬관절의섬유성활막에서분리한지방줄기세포가피하지방에서분리한세포에비하여연골및골로의분화능력이높다. 27) 같은피하지방이라고하더라도복부피하지방보다도엉덩이부분에서분리한지방줄기세포가골분화능력이높다. 28) 지방줄기세포의분리법 지방기질맥관구획 (adipose stromal vascular fraction) 에서부터의세포분리는 1960 년도이미행해졌다 ) Zuk 등은지방조직으로부터효소처리방법을이용하여지방줄기세포를분리하였으며효소분리후플라스틱표면에세포가붙어자라는성질을이용하는것이아직까지지방줄기세포분리법의근간이되고있다. 32) 대부분 collagenase I 을이용하나적용농도와온도는연구자마다차이가있다. 그외다른방법으로서는수용치양성을 cell sorting 을이용해서분리하여연골및골분화능력이향상된세포의군집을얻었다는보고가있으며 33) 연속된원심분리로두개의독립된세포군을얻어분리하였다는보고가있다. 34) 또한 CD34 + /CD31 인세포를여러다른항체가부착된 immunomagenetic bead 를이용하여분리하는방법도있다. 35) 또한종래의원심분리법의최적화에대한여러연구가진행되었는데 1200 g 가가장많은지방줄기세포를얻을수있는농도이며 3000 g 이상으로할경우세포가손상받는다. 16) 또한현재사람에서지방줄기세포를얻기위하여가장많이쓰이는방법인지방흡인술은그자체가지방조직을잘게자름으로서세포의분리를쉽게만드는점이있는데부피가큰지방세포가손상되지만체적이작은지방줄기세포는손상을받지않는다는연구가있다. 28) 지방줄기세포표현형의동정 지방줄기세포의표면에는 HCA-ABC, CD29, CD49e, CD51, CD90 등의표지자가일관되게표현되며 CD49d, CD9, CD34, CD105, CD166은 50% 이하의발현을보인다고한연구가있으나 36) 본연구자의결과에서는 CD73, CD90, CD166 등간엽줄기세포의표지자로알려진표지자들이 90% 이상발현되나 TGF-β의수용체인 CD105(endoglin) 은 40% 정도로골수줄기세포에비하여낮은수치를보였다. 23) 이러한표지자들은계대배양을거치며변할수있으나 2차계대배양이후는안정된것으로알려져있다. 37) 지방줄기세포의분화능력 지방줄기세포는연골, 골, 지방세포외에도신경, 심근세포, 근세포, 혈관내피세포, 간세포로분화될수있다. 본논문에서는주로골과연골의분화에대한내용을정리하고자한다. 대부분의연구에서지방줄기세포는골수줄기세포와동일한조건하에배양하였을때배양 2-4주내에골모세포로분화하고 3,5) 배지의조성이분화에매우중요하며, 배양액에는 β-glycerophosphate 와 dexamethasone 이포함되어있어야하며또한 1, 25-dihydroxyvitamineD 3, BMP-2 가분화유도를촉진시키며 38-40) growth and differentiation factor T (GDF-5) 는 BMP-2 보다도더강력하게골모세포로의분화를촉진시키며 VEGF의유도도촉진시킨다. 41) 연골분화에있어서 TGF-β와 ascorbate, dexamethasone 의투여가연골로의분화를촉진시키지만골수줄기세포보다는훨씬동일한용량을투여하였을때분화정도및연골기질생성정도가떨어지며본연구자들의연구에따르면 TGF-β 2 를 25 ng/ml, IGF-I을 500 ng/ml 정도로고농도를투여한경우와 TGF-β 2 를 100 ng/ml 의 BMP-2 나 BMP-7을같이투여한경우연골생성이골수줄기세포와비슷한정도로형성되었다. 22,23) 그러나 Estes 등에의하면 BMP-6가 BMP-7 보다더낮은온도에서연골형성을촉진함을보고하여다른결과를보였고 42) FGF-2가연골형성의조절전사인자인 SOX-9의발현을촉진하였다는보고도있다. 43) 지방줄기세포의면역반응 지방줄기세포는 MHC-II, CD40, CD80, CD86과같은면역반응을유발하는유전자는없는것으로알려져있으며골로분화한다음에도이러한인자를표현하지않는다. 44) 또한다른사람의림프구와같이배양했을때림프구의증식이억제되었다. 그억제정도는세포수가많아질수록, 지방줄기세포와의접촉시간이길수록더증가하였다. 또한바로분리한세포의경우에는 T림프구증식반응을유도한다 ) 지방줄기세포를이용한골조직공학 골조직분야에서여러연구들이진행되어지방줄기세포가대부분의생체재료의표면에잘부착되고골모세포와유사한세포로분화됨이알려졌다. 47) Peterson 등은 Collagen-세라믹지지체에 BMP-2 가이입된지방줄기세포를생주의대퇴골한계결손에이식하였을때지방줄기세포가새로운골을형성하면서대퇴골결손이치유됨을관찰하였다. 48) Hattori 등은 Β-TCP 지지체를이용하여골수줄기세포와지방줄기세포간에골형성능력을비교하였는데생쥐의등에이식하였을때골형성능력의차이가없음을관찰하였다. 49) Kakudo 등은벌집모양콜라겐지지체에지방줄기세포의분 Biomaterials Research 2009

3 지방줄기세포를 이용한 조직재생의 현황 화를 유도하여 지방줄기세포가 골모세포 모양으로 분화하여 골 모세포의 특유한 유전자를 생성하며 기질을 형성함을 보고하였 다. 게다가 최근에는 지방줄기세포가 VEGF를 생성하며 지지체 내에 내피세포의 성장을 촉진시키는 점도 밝혀졌다.50) 지방줄기세포를 이용한 연골 조직공학 지방줄기세포도 골수 줄기세포와 유사하게 형태로 3차원 배 79 양을 할 경우 연골의 성질을 가지는 조직으로 분화할 수 있다 고 생각되고 있다 (Figure 1).51) 본 연구자는 지방줄기세포를 골수줄기세포와 같은 조건인 5 ng/ml 의 TGF-β2 를 투여하였을 경우 연골형성 능력이 낮음을 관찰하였다.24) 최근의 연구에서 100/ml 의 BMP-2와 BMP-2을 같이 쓸 경우 또는 25 ng/ml 의 TGF-β2 와 500 ng/ml의 IGF-I을 투여할 경우 골수줄기세포 에서 볼 수 있는 정도의 연골형성이 가능함을 관찰하였다 (Figure 2, 3).22,23) 최근 Dragoo 등은 지방줄기세포를 fibrin glue에 섞어 토끼의 연골 결손을 치유함을 관찰하였다.52) 앞으로의 전망 지방줄기세포의 재생의학에의 이용에 대하여 2001년 이후 폭발적으로 많은 연구가 진행되었고 많은 지식이 밝혀졌으나 임상적으로 쓰일 수 있는 정도에 도달하기 위하여는 면역반응, 분화능력에 대하여 상당한 수준의 연구가 더욱 진행되어야 할 것으로 사료된다. 감사의 글 이 논문은 2008년도 보건의료기술 개발사업(A080326)의 지 원을 받았으므로 이에 감사드립니다. 참고문헌 Figure 1. Scheme of cartilage tissue engineering using adipose stem cells. 1. J. M. Gimble, A. J. Katz, and B. A. Bunnell, Adipose-derived stem Figure 2. Safranin-O staining from adipose stem cells cultured for 3 weeks in pellets under different chondrogenic medium ( 100). TGF (transforming growth factor)-β2 (5 ng/ml) combined with BMP(bone morphogenetic protein)-2 (100 ng/ml) or BMP-7 (100 ng/ml), or the combinations of high dose TGF-β2 with high dose IGF(insulin-like growth factor)-i yielded good results. N: no growth factor, I: IGF 100 ng/ml, T: TGF-β2 5 ng/ml, B2:BMP ng/ml, B6:BMP ng/ml, B7:BMP ng/ml, T+B2: TGF-β2 5 ng/ml plus BMP ng/ml, T+B6: TGF-β2 5 ng/ml plus BMP ng/ml, T+B7: TGF-β2 5 ng/ml plus BMP ng/ml, T+I100: TGF-β2 5 ng/ml plus IGF-I 100 ng/ml, T+I300: TGF-β2 10 ng/ml plus IGF-I 300 ng/ml, T+I500: TGF-β2 15 ng/ml plus IGF-I 500 ng/ml, BM: bone marrow derived mesenchymal stem cells culred under 5 ng/ml of TGF-β2. Vol. 13, No. 3

4 80 임군일 Figure 3. RT-PCR from the pellets cultured for 3 weeks under different chondrogenic medium shows that the expressions of chondrogenic genes (type II collagen, SOX-9) increased when TGF-β 2 combined BMP-7, or the combinations of high dose TGF-β 2 with high dose IGF-I was treated. N: no growth factor, I: IGF 100 ng/ml, T: TGF-β 2 5 ng/ml, B2: BMP ng/ml, B6: BMP ng/ml, B7: BMP ng/ml, T+B2: TGF-β 2 5ng/ml plus BMP ng/ml, T+B6:TGF-β 2 5 ng/ml plus BMP ng/ml, T+B7: TGF-β 2 5 ng/ml plus BMP ng/ml, T+I100: TGF-β 2 5 ng/ml plus IGF-I 100 ng/ml, T+I300: TGF-β 2 10 ng/ml plus IGF-I 300 ng/ml, T+I500: TGF-β 2 15 ng/ml plus IGF-I 500 ng/ml, BM: bone marrow derived mesenchymal stem cells culred under 5 ng/ml of TGF-β 2. cells for regenerative medicine., Circ. Res., 100, (2007). 2. A. M. Rodriguez, C. Elabd, E. Z. Amri, G. Ailhaud, and C. Dani, The human adipose tissue is a source of multipotent stem cells., Biochimie, 87, (2005). 3. J. Gimble, and F. 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Biomaterials Research (2007) 11(3) : 91-95 Biomaterials Research 7 The Korean Society for Biomaterials w» s w š A Brief Review on Adipose Tissue-Derived Mesenchymal Stem Cells * Gun-Il Im* Š f