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1 Korean J Gastroenterol Vol. 58 No. 3, REVEIW ARTICLE 질병치료제로서줄기세포의특성 서검석 원광대학교의과대학내과학교실, 소화기질환연구소 Stem Cell Properties of Therapeutic Potential Geom Seog Seo Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea Stem cell research is a innovative technology that focuses on using undifferentiated cells able to self-renew through the asymmetrical or symmetrical divisions. Three types of stem cells have been studied in laboratory including embryonic stem cell, adult stem cells and induced pluripotent stem cells. Embryonic stem cells are pluripotent stem cells derived from the inner cell mass and it can give rise to any fetal or adult cell type. Adult stem cells are multipotent, have the ability to differentiate into a limited number of specialized cell types, and have been obtained from the bone marrow, umbilical cord blood, placenta and adipose tissue. Stem cell therapy is the most promising therapy for several degenerative and devastating diseases including digestive tract disease such as liver failure, inflammatory bowel disease, Celiac sprue, and pancreatitis. Further understanding of biological properties of stem cells will lead to safe and successful stem cell therapies. (Korean J Gastroenterol 2011;58: ) Key Words: Pluripotent stem cell; Multipotent; Digestive tract disease; Stem cell properties 서론 줄기세포 (stem cell) 는미분화세포로서대칭적 (symmetrical) 또는비대칭적 (asymmetrical) 인세포분열방식을통해특정한기능을가지는세포로분화및자가재생산 (self-renewal) 을유지할수있는데, 자가재생산이란미분화성과다중분화능 (multipotent) 을가진줄기세포를세포분열을통해재생산하는과정을말한다. 1,2 줄기세포는태아의발생과정중모든조직에존재하고, 성인에서는골수, 상피조직등일부조직에서발견되고있다. 1998년최초로인간배아줄기세포배양이성공한이후, 3 줄기세포에대한관심이높아지고있는데, 줄기세포는크게배아줄기세포 (embryonic stem cells), 성체줄기세포 (adult stem cells), 유도만능줄기세포 (induced pluripotent stem cells, ipscs) 로구분할수있다. 줄기세포는분화가능한세포의종류에따라수정란이첫분열을시작 할때형성되는전능성줄기세포 (totipotent stem cell), 초기수정란세포가분열하면서여러장기로분화되기전단계의세포로서태아나성체의모든세포로가는만능성줄기세포 (pluripotent stem cell), 제한된장기로만분화가가능한다능성줄기세포 (multipotent stem cell) 로분류할수있다. 줄기세포를이용한세포치료는퇴행성, 난치성질환을앓고있는많은환자들에게희망이되는치료법이기도하지만, 배아줄기세포를이용한치료의경우인간배아를사용해야하는생명윤리적논란과함께종양발생의가능성이있다는것이문제점으로지적되고있다. 소화기관련질환중염증성장질환, 셀리악병 (celiac disease), 급성간부전, 간경변, 광범위간절제술후간부전, 췌장염등에대해줄기세포치료를시도하여일부효과를보고있으나, 미분화상태의지속유지를위한작용기전, 분자생물학적이해, 유전형에따른줄기세포확보, 면역거부반응해결등더많은연구가필요한상 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 서검석, , 전북익산시신용동 344-2, 원광대학교의과대학내과학교실, 소화기질환연구소 Correspondence to: Geom Seog Seo, Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, 344-2, Shinyong-dong, Iksan , Korea. Tel: , Fax: , medsgs@wonkwang.ac.kr Financial support: This paper was supported by Wonkwang University in Conflict of interest: None. Korean J Gastroenterol, Vol. 58 No. 3, September

2 126 서검석. 질병치료제로서줄기세포의특성 황이다. 이번원고에서는줄기세포의일반적특성및소화기영역과관련된줄기세포의세포학적특성에대해서기술하고자한다. 본론 1. 줄기세포의일반적특성 1) 배아줄기세포 (embryonic stem cells) 인체의모든세포를만들어낼수있는전능성줄기세포 (totipotent stem cell) 인수정란은여러차례의세포분열을거쳐배반포 (blastcyst) 를형성한다. 배반포는영양배엽세포 (trophoblast cell) 와인체를형성할수있는내부세포괴 (inner cell mass) 로구분하는데, 줄기세포를얻기위해서는내부세포괴만을분리해야한다. 내부세포괴는모든필요한세포로분화하지만완전한기관을형성하지는못하는다능성줄기세포 (pluripotent stem cells) 로구성되어있으며, 주위환경인자의영향을받아내배엽 (endoderm), 중배엽 (mesoderm), 외배엽 (ectoderm) 으로분화한다. 마우스의배아영양세포층 (mouse embryonal feeder layer, MEF) 을이용하여내부세포괴를공동배양 (co-culture) 하면 3-5일후부터콜로니 (colony) 형성을관찰할수있다. 4 원형의콜로니및세포핵이 70% 이상인세포의형태를보이면줄기세포로판정하고확립된세포에대한염색체분석, 세포표면특이항체발현, 삼배엽성세포분화, 특이유전자발현, 생체이식후테라토마 (teratoma) 형성을확인하여인간배아줄기세포를확립할수있다. 5 배아줄기세포의자가재생산을위해서는외부적및내부적신호전달이외에도 Chromatin 리모델링, 6,7 마이크로 RNA (microrna), 8,9 telomere reverse transcriptase (TERT) 10,11 등이관여하는데, 외부적신호전달에는 leukemia inhibitory factor (LIF), 12,13 Wnt, 14,15 fibroblast growth factor (FGF), 3,16-19 bone morphogenic protein (BMP) 20 가, 내부적신호전달에는 octamer-binding transcription factor4 (Oct4), 21,22 Nanog, forkhead box O1 (FOXO1) 26 이있다. 마우스와인간배아줄기세포의자가재생산기전의차이점은인간에서는 LIF가아닌 FGF 신호전달에의해유지된다는것이다. 3,27 2) 성체줄기세포 (adult stem cells) 비교적짧은기간의배아줄기세포연구에비해, 성체줄기세포연구는수십년전부터이루어져왔으며, 28 주요치료대상은심혈관계질환 ( 심근경색, 심부전 ), 암, 혈액질환 ( 백혈병, 림프종 ) 및뇌질환 ( 뇌졸중, 알츠하이머병 ) 등이다. 성체줄기세포는골수, 제대혈 (umbilical cord blood), 태반, 혈액, 피부, 지방조직, 신경조직, 간, 췌담도등에서추출한줄기세포의집합체를의미한다. 성체줄기세포의종류중에서가장많 이연구가이루어진것은조혈모세포 (hematopoietic stem cell) 이고, 그외에재생의학의재료로각광받고있는중간엽줄기세포 (mesenchymal stem cell), 신경줄기세포 (neural stem cell) 등이있다. 체외증식의한계로인하여많은양의미분화세포를얻을수없고, 분화능력측면에서도배아줄기세포에비해제한적이라는단점이있지만, 윤리적인문제가없고, 조직접합성을고려하여추출하면면역거부반응도해결할수있는장점이있다. 성체줄기세포의특성으로는자가재생산, 비대칭분열, 분화유연성 (plasticity) 을들수있다. 비대칭분열이란줄기세포가자기복제를유지해가면서다른세포로분화하는것을말한다. 이에비해전구 (progenitor) 세포는자가재생산은없으면서다른세포로분화, 분열만을하는대칭분열을하게된다. 29 분화유연성은한개의특수한조직형을띤세포가원래기대되었던세포가아닌다른세포로분화가이루어지는것을의미하는데, 혈액세포에서간세포및심장세포로의분화가대표적인예다. 30,31 CD34, CD38, CD133, c-kit, thy-1 등의표면항원형을보이는조혈모세포 32 분화의유연성은간및심장근육에만국한된것이아니라, 연골세포, 신장세포, 근육세포, 뇌세포등으로분화될수있다. 33 골수에서비부착세포가조혈모세포인반면, 부착세포는골수의기질세포를구성하는중간엽줄기세포라할수있는데, 제대혈줄기세포나지방줄기세포등도여기에포함된다. 34,35 3) 유도만능줄기세포 (ipscs) 2006년과 2007년에마우스와인간체세포의인위적리프로그래밍 (reprogramming) 에의해이미분화된세포들이초기미분화상태로되돌아가는역분화 (dedifferentiation) 현상을증명하였는데, 마우스체세포에배아줄기세포의특성을유지하는 24개의후보유전자들중에 Oct4, region Y-box 2 (Sox2), Krüppel-like factor4 (Klf4), c-myc 등 4개의유전자를선별하여레트로바이러스 (retrovirus) 에도입및발현시켜만능성 (pluripotency) 세포를만들었고, 36 인간체세포에서도신경세포, 심장세포로분화가능하다는것을증명하였다. 37 역분화유도에대한연구는핵이식으로탄생한복제양돌리와 38 배아줄기세포와섬유아세포를융합하였을때섬유아세포가리프로그래밍과정을통하여만능성을재획득하는과정을통해 39 난자및배아줄기세포내에역분화인자가존재한다는것을알수있다. 역분화를유도하기위해바이러스를사용해야하는문제점이있지만, 자기자신의세포를추출하여체외배양을통해무한증식이가능하고, 원하는세포를대량생산할수있으므로, 거부반응이없고자가재생산및분화능력이좋아, 환자특이적유전질환및난치병치료에활용될것으로기대하고있다. 40 The Korean Journal of Gastroenterology

3 Seo GS. Stem Cell Properties of Therapeutic Potential 소화기관련영역에서줄기세포의특성 1) 위장관줄기세포 (gastrointestinal stem cells) 태생학적으로위장관계는내배엽 (endoderm) 에서기원하며, 배아중층상피 (embryonic stratified epithelium) 는점차적으로융모를덮는단층으로전환된다. 장음와 (crypt) 는산후초기에위장관줄기세포의미세환경 (niche) 이된다. 구조가만들어지면장관을덮고있는상피는구조-기능적특성과증식동력적 (proliferation kinetics) 측면에서서로이질적인구성이되어다른기능을나타내게된다. 41,42 대부분의상피는 2-5일만에교체가되는데, 이는조혈기관에이어두번째로높은증식률을보이는것이다. 43 장의자가생산력은장음와와위선에존재하는다중분화능위장관줄기세포에의해결정되는데, 44,45 장줄기세포는 Lieberkuhn 음와의기저부위에위치하고있다. 미세환경에서장줄기세포는비대칭적분화방법을통해전이증폭세포 (transit-amplifying cell) 가된다. 이러한장전구세포는상층으로이동하여성숙되고, 동시에고유의증식능은소멸되어최종적으로완전분화된융모성상피세포가된다. 43 위에서줄기세포는위선의경부와협부 (isthmus) 부위에있는것으로보고하고있는데, 이동은양방향이어서, 상부로는소와 (foveola) 로이동하여점막상피를형성하고아래로는위선의기저부로이동하여벽세포 (parietal cell) 와주세포 (chief cell) 를이루게된다. 44,45 대장염동물모델마우스에골수세포를투여하면골수세포가위장상피에콜로니를형성하고재구성할수있으므로위장관계질환에서골수유래줄기세포를질환의치료에적용해볼수있을것이다. 46,47 골수줄기세포가위장관골수세포의역할을담당할뿐만아니라, 근섬유모세포 (myofibroblast) 와같은지지요소를제공해줌으로써장관손상회복에참여하여장관회복에관여할것으로생각하고있다. 위장관줄기세포의분자특성은아직잘파악하고있지못하지만, 위장관줄기세포의증식및분화를조절하는상피-간질세포의신호전달이중요할것으로생각하고있다. 대장염에대한 CD34 줄기세포, 48 기능성질환에대한 CD34 + /c-kit low+ 카할간질세포 (interstitial cell of Cajal) 관련줄기세포연구가흥미를끌고있으며, 49 향후이분야에대한더많은연구가필요할것이다. 2) 간줄기세포 (hepatic stem cells) 간은간세포, 담관세포외에도쿠퍼세포, 간성상세포 (hepatic stellate cell), 혈관내피세포로구성되어있고, 문맥내담관은문맥역내에국한되나, 말단담도세관인 canal of Hering은간내담관을간세포삭 (hepatic cord) 과연결시킨다 (Fig. 1). 50 간세포삭은모세혈관과모세혈관사이의간세포가일렬로줄지어배열되어있는모양을말하며, 1990년대초까지는장상피세포와같이줄기세포가간세포삭의문맥주변부 에서분열하여서서히중심정맥쪽으로이동해가면서수명을다한다는 stream liver 가설 이제기되었으나, 51,52 후속실험에서정상간세포가인접한판의여러개에걸치는자손세포 (progeny) 를형성하고, 중심정맥으로이동하지않는다고증명하였다. 53 간에는성숙한간세포와난원세포 (hepatic oval cell, hepatic progenitor cell) 라는두종류의줄기세포가있으며, 이가운데성숙한간세포는높은재생력으로자가증식함으로써간재생에중요한역할을하기때문에과거부터줄기세포로불리워졌다. 부분간절제, 사염화탄소 (CCl 4) 또는 galactosamine 손상을입은간에서는손상된간세포를복원하기위해중심정맥주위부에위치한간세포에서재생이일어난다. 54,55 간내줄기세포는 canal of Hering에위치하며난원세포로불리는데, 핵이크고세포질이적다. 사염화탄소 /2-acetylaminofluorene (2-AAF) 또는 Furan과같은약물로인해중심정맥성간세포손상을심하게받게되면, 간세포와담관상피세포로증식할수있다. 간내줄기세포는발달과정에따라다양한특징을보이고있고 (Fig. 1), 50 간실질세포와중간엽세포간의상호조절에있어서주요한형태는측분비신호전달 (paracrine signaling) 로, 세포상호간의작용을통하여각각의발달단계를조절하게된다 (Fig. 2). 50 간난원세포의반응을활성화, 증식, 이동, 분화의 4 단계로나눌수있으며, 몇가지인자가이에관여하는것으로알려져있으나 (Fig. 3), 56 세포들이만들어내는물질이무엇이며또한어떠한신호전달을받는지는추후연구가필요하다. 간외줄기세포 (extra-hepatic stem cell) 의공급원으로배아줄기세포, 성체줄기세포중조혈모세포와중간엽줄기세포, 그외에만능분화줄기세포가이용될수있다. 손상받은간에조혈모세포를투여하면, 간세포로전위분화 (transdifferentiation) 되어간분화및증식이증가한다는주장이있는반면, 전위분화한골수세포의빈도와효능성이낮고분화속도가느려, 간세포내에서융합 (cell fusion) 현상에의해간세포가발생한다는다른의견도제시되고있다. 60,61 3) 췌장줄기세포 (pancreatic stem cells) 췌관조직을배양하여췌도전구세포 (islet progenitor cell) 를증폭하고베타세포로분화, 유도하는연구가이루어진후, 62,63 마우스로부터무혈청, 집락-형성분석법 (serum free, colony-forming assay) 을통해췌장줄기세포를동정하여신경세포와췌장세포로분화할수있는다능성을갖는전구세포분리까지가능하게되었다. 64 Cytokeratin19 (CK19) 와 pancreatic and duodenal homeobox1 (PDX1) 을발현하는췌관세포 (pancreatic duct cell) 와췌도세포 (islet of Langerhans) 는내분비기능을가지는췌도세포로분화가능하며, 65,66 nestin-positive islet-derived progenitor cells (NIPs) 의경우 Vol. 58 No. 3, September 2011

4 128 서검석. 질병치료제로서줄기세포의특성 Fig. 1. Structure of the hepatic lobule. The portal triad consists of bile ducts, hepatic artery, and portal vein. 50 Mixed blood from the hepatic artery and portal vein flows past hepatocytes through the sinusoids, covered with fenestrated endothelial cells to the central vein. Bile produced by the hepatocytes is collected in the bile canaliculus and flows towards the bile duct. The Canal of Hering is the junction between the hepatic plate and the bile ducts. This is the region where oval cell precursors reside. 50 ATP-binding cassette transporter를발현한다. 67,68 HGF (hepatocyte growth factor) 는베타세포의발생, 기능, 분화, 증식을조절하며, 69 c-kit은췌도세포와유사한전구체에서발현되어관련표지자로생각하고있다. 70,71 췌장주위장기기원줄기세포중에서, 간세포, 72,73 사람지방세포유래중간엽줄기세포, 74 장줄기세포 75 등이췌도세포로 분화할수있다. 분화된베타세포로부터분비되는인슐린의양이적어이를극복하기위한기술적향상과더많은기능연구가필요하다. 최근에는중간엽줄기세포를이용하여췌장염치료에좋은효과를보인다는연구도있어 76 이에대한추가적인연구도필요할것이다. The Korean Journal of Gastroenterology

5 Seo GS. Stem Cell Properties of Therapeutic Potential 129 Fig. 2. Schematic image indicating the coordinate maturation of the epithelia (parenchymal cells) and their mesenchymal partners and some of the identified extracellular matrix components found at the particular lineage stages. 50 Not shown in the figure are the soluble signals that also are lineage dependent. Some of the lineage dependent soluble signals identified are noted in parentheses beside the lineage stage at which they are found: hepatic stem cells (LIF, IL-6, IL-11, and acetylcholine); hepatoblasts (HGF, EGF, βfgf, IL-6, IL-11, and acetylcholine); hepatocytes (HGF, EGF, βfgf, T3, glucagon, and hydrocortisone); cholangiocytes (VEGF, HGF, βfgf and acetylcholine). 50 Fig. 3. Signaling events during the hepatic oval cell response. 50 A time line representing the stages of oval cell activation, proliferation, migration, and differentiation. The factors that are involved in each stage of the response are listed at the bottom. 56 LIF, Leukemia inhibitory factor; OSM, Oncostatin M. 결론 배아줄기세포, 성체줄기세포, 유도만능줄기세포를이용한세포치료연구는난치성질환을해결하고자하는측면에서볼 때, 흥미로운연구분야라고할수있다. 분화유연성및다중분화능에대한연구가진행중인성체줄기세포는배아줄기세포와는상이한세포학적특성을가지므로, 다른측면으로접근해야하며, 아직밝혀지지않은생물학적특성을찾는것이 Vol. 58 No. 3, September 2011

6 130 서검석. 질병치료제로서줄기세포의특성 과제로남아있다. 소화기분야의여러질환에줄기세포치료법을도입하고자하는시도가이루어지고있으나, 아직까지는시작단계라할수있다. 안전한치료법으로인정받기위해서는장기추적관찰시세포치료법으로서안정성, 관용성 (tolerability), 효율성을가질수있어야하고또한암으로의형질전환 (transformation) 등의문제도해결하여야만진정으로질환의치료와예방에폭넓게사용될것이다. REFERENCES 1. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell 1997;88: Blank U, Karlsson G, Karlsson S. Signaling pathways governing stem-cell fate. Blood 2008;111: Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282: Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A 1981;78: Chung HM. Clinical application of human embryonic stem cells. J Korean Med Assoc 2011;54: Hattori N, Nishimo K, Ko YG, et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. 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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract