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1 대한내과학회지 : 제 89 권제 5 호 의학강좌 - 개원의를위한모범처방 (Current Clinical Practice) 호흡기질환에서의중간엽줄기세포의치료 고려대학교의과대학내과학교실호흡기내과 이은주 Mesenchymal Stem Cell Therapy in Pulmonary Disease Eun Joo Lee Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Stem cells are undifferentiated cells that are clonal, self-renewing, and can differentiate into multiple cell types (known as potency). Among stem cells, there are embryonal stem cells, induced pluripotent stem cells, mesenchymal stem cells (MSCs), and hematopoietic stem cells. MSCs are fibroblast-like non-hematopoietic stem cells that can differentiate into various tissue types, including bone, muscle, liver, lung, and cartilage. MSCs can be isolated from bone marrow, adipose tissue, placenta, or umbilical cord blood, among other tissues. MSCs are adherent under tissue culture conditions and express several cell surface markers, including CD105, CD73, and CD90. However, MSCs show negative expression for CD45, CD34, CD14, CD11b, CD79α, CD19, and HLA-DR. This article aims to explain the current definition of MSCs, describe therapies for which MSCs may be used, and review recent lung disease clinical trials. (Korean J Med 2015;89: ) Keywords: Mesenchymal stem cells; Mechanism; Clinical trials 서론중간엽줄기세포 (mesenchymal stem cell) 는 1968년 Friedenstein 에의해골수에서처음분리되었으며, 조혈모세포 (hematopoietic stem cell) 와는달리 fibroblast처럼생겨플라스틱배양용기에달라붙는성질이확인되었다 [1]. 이후중간엽줄기세포는제대혈, 태반, 지방조직, 양수등인체의여러장기에서분리되었다 [2]. 중간엽줄기세포는타인의난자를사용해야하는배아줄기세포 (embryonic stem cell) 와는달리윤리적문제에서자유로우며, 이식후면역거부반응 이거의없다. 한편성체세포를거꾸로되돌려미분화상태의세포로만든역분화줄기세포 (induced pluripotent stem cell) 는역분화유도를위해레트로바이러스나렌티바이러스를이용해야한다는단점과함께배아줄기세포와유사하게암유발가능성도있어현재의시점에서환자에게바로적용하기에는한계가있다 [3]. 반면중간엽줄기세포는비교적배양하기가쉽고많은양의세포를증식시킬수있어, 현실적으로임상에서가장먼저치료제로시도해볼수있다는장점이있다. 이번글에서는호흡기질환에서의중간엽줄기세포의정 Correspondence to Eun Joo Lee, M.D., Ph.D. Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea Tel: , Fax: , nanjung@korea.ac.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Eun Joo Lee. MSC in pulmoary disease - 의, 치료효과의기전및임상시험내용을중심으로최신지견을기술하고자한다. 정의 본 줄기세포 (Stem cell) 는다음의세가지를특징으로하는미분화된세포로, 첫째자가재생 (self re-newal) 이가능하며, 둘째하나의세포에서발생한클론성을지니며, 셋째다른세포나장기로의분화가가능하다 [3]. 줄기세포는다시수정란의발생초기에얻게되는배아줄기세포와발생과정후발견되는성체줄기세포 (adult stem cell) 로나뉜다 [4]. 성체줄기세포중가장오랫동안연구되고골수이식으로임상경험이비교적많이축적된것이조혈모세포이다. 조혈모세포가주로부유상태 (non-adherent) 로있는세포라면, 중간엽줄기세포는부착성상태로있다. 중간엽줄기세포는최소한다음의세가지조건을충족하여야한다 (Table 1). 첫째, 배양용기에부착되어증식되어야한다. 둘째, 특정세포표면항원이발현되거나발현되지않아야한다. 즉, 특정세포표면항원으로 CD105, CD73, CD90 이존재하여야하며, 조혈모세포항원인 CD45, CD34, CD14, CD11b, CD79α, CD19 또는 HLA-DR 항원등은없어야한다. 셋째, 시험관내에서골모세포, 지방세포, 연골모세포로분화할수있어야한다 [5]. 중간엽줄기세포에는골수줄기세포, 제대혈줄기세포, 지방줄기세포, 신경줄기세포등이있다 [6]. 중간엽줄기세포의치료기전 정착및분화 (Engraftment and transdifferentiation) 여러종류의중간엽줄기세포는특히폐특이적분화유도배지 (lung-specific differentiation media) 에노출시폐포의상피세포등비혈액학적조직 (non-hematopoietic tissues) 으로의 Table 1. Three primary biological criteria for mesenchymal stem cells Adherence to plastic under tissue culture conditions. Positive expression of CD105, CD73, and CD90. Negative expression of CD45, CD34, CD14, CD11b, CD79α, CD19 or HLA-DR. In vitro differentiation into osteoblasts, adipocytes, and chondroblasts. 론 분화가가능한것으로알려져있다 [7-9]. 줄기세포에서특정장기로의분화가가능하다는연구결과가나오면서향후장기이식을대체할수있을것이라는기대도쏟아져나왔다. 하지만중간엽줄기세포를정맥혹은기관내투여시실제폐에서의정착 (engraftment) 의비율이매우낮다는연구결과가발표되면서, 투여한중간엽줄기세포가상피세포로직접적으로재생될것이라는소견에대해서는다소회의적인견해가우세한실정이다 [10-14]. 주변분비작용 (Paracrine effect) 줄기세포를투여후생체에서의정착률이기대보다낮은것으로밝혀지면서, 주변분비작용 (paracrine effect) 의중요성이부각되기시작하였다. 여기에는대식세포군집자극인자 (macrophage colony-stimulating factor), 과립성백혈구대식세포군집자극인자 (granulocyte-macrophage colony-stimulating factor) 와같은조혈세포사이토카인및혈관내피성장인자 (vascular endothelial growth factor), 간세포성장인자 (Hepatocyte growth factor), TGF-β1 를포함한성장인자들, TNFα, IL-1, IL-6 와같은싸이토카인이포함되어있다 [15]. 예를들어산소가부족한상황에서의줄기세포투여는혈관내피성장인자의분비를증가시키고, 이는다시내피세포의수적증가및사멸세포의감소를각각유도한다 [16]. 즉, 줄기세포가손상된폐를대체하거나폐세포로직접분화재생되기보다는여러가지물질들을분비하여궁극적으로는폐세포를각종손상으로부터보호한다는기전이다 [13]. 면역조절작용 (Immunomodulatory effect) 줄기세포치료로이식편대숙주병 (Graft versus host disease) 을호전시킬수있음이밝혀진뒤, 중간엽줄기세포의면역조절작용이학자들의관심을끌었다 [17]. 중간엽줄기세포는 B형및 T형림프구, 수상세포 (dendritic cell) 를억제하고, IL-10을통한조절 T형림프구의촉진등을통해선천면역체계 (innate immune system) 와적응성면역체계 (adaptive immune system) 모두에직접적으로작용할수있다 [18]. 이과정에서중간엽줄기세포자체가항원제시세포 (antigen presenting cell) 의역할도수행한다. 한편, 줄기세포는면역세포뿐만아니라주위의구조를구성하는세포에도영향을줄수있는 episomal 혹은 microsomal particle 을분비하는것으로알려져있다 [14]. 그외에도심근경색, 당뇨병, 중풍등의많은질환에서증가된염증반응이관찰되며, 줄기세포치료가이비정상적으로증가된염증을조절하여이들질환을효과적으로제어할것으로예측하고있다 [19]

3 - 대한내과학회지 : 제 89 권제 5 호통권제 663 호 주요임상시험연구들중간엽줄기세포를이용하여각종난치성호흡기질환을치료하려는임상시험연구는여전히부족한실정이며, 그치료효과또한만족스럽지못한것이사실이다. 지금까지수행되어발표된각종임상시험연구들을표 2에정리하였다. 만성폐쇄성폐질환 (COPD) 만성폐쇄성폐질환은비가역적인기류제한을특징으로하는폐질환으로, 만성적인염증으로인하여기도와폐실질에손상이야기되는질환이다. 세계적으로 1990년에는사망원인 6위의질환이었지만, 2020년에사망률 3위의원인질환이될것으로우려된다 [20]. 만성폐쇄성폐질환에서의첫줄기세포임상연구는 2009년브라질에서시행되었다 [21]. 1상연구로, 동원가능한현재의치료에호전이없고여명이얼마남지않은환자 4명을대상으로하였다. 환자자신의골수에서줄기세포를채취한후바로정맥을통해 1회투여하였으며, 이후 12개월간추적관찰하였다. 그결과줄기세포투여에의한심각한부작용은관찰되지않았으며, 삶의질향상및일시적인폐기능의호전도보였다. 이후 62명의중등도및중증의만성폐쇄성폐질환환자를대상으로진행된연구가발표되었다 [22]. 총 6개기관에서진행된, 무작위, 맹검연구로, 월 1회골수줄기세포를정맥주사로총 4회투여한뒤 2년간추적관찰하였다. 연구중줄기세포의투여와관련된심각한부작용은없었다. 투여초기에 C-reactive protein 의감소를보였으나, 그외폐기능, 삶의질, 6분도보검사, 염증반응등의결과는대조군과유의한차이가없었다. 그외에도소 수의임상연구들이진행중이거나종료후발표를앞두고있다 [23]. 급성호흡곤란증후군급성호흡곤란증후군은다양한원인에의해폐포- 모세혈관사이의투과성이증가되어폐포내에삼출액이차고, 여러가지염증반응이일어나면서결국저산소증을초래하는임상증후군이다. 원인질환에이환된지일주일이내에발병하여흉부방사선검사상양측성폐침윤이관찰되며, PaO 2/ FiO 2 비율이 300 mmhg 이하인경우로정의한다 [24]. 현재까지발표된임상연구는 1건으로, 중국의한기관에서 12명의환자를대상으로무작위배정, 맹검으로시행되었다 [25]. 타인의지방줄기세포를 1회투여한뒤 28일간추적관찰하였다. 다른질환에서의연구들과유사하게투여와관련된부작용은없었으며, 입원기간, 인공호흡기제거기간등의임상적인효과는뚜렷하지않았다. 다만혈청에서급성폐손상의지표중하나인 Surfactant protein D가투여 5일째유의하게감소하는소견을보였다. 특발성폐섬유화증특발성폐섬유화증은폐에국한되며점차만성적으로진행하는섬유화를특징으로하는희귀질환이다. 아직까지이질환을호전시키는것으로밝혀진약물치료는없으며, 생존율을높이는것으로확인된치료는폐이식이유일한실정이다 [26,27]. 첫임상연구는그리스의한기관에서총 14명의심하지않은특발성폐섬유화증환자를대상으로진행하였다 [28]. 지방줄기세포를기관지내시경을이용하여기관지 Table 2. Published clinical trials using MSCs in respiratory diseases Disease Patients Cell type Dose Frequency Route Conclusion Reference COPD 4 BMMC 30 ml 1 IV No serious S/E 21 More clinical stable condition 62 BM-MSC IV No serious S/E 22 Decreasing CRP, Otherwise non-remarkable ARDS 12 AD-MSC /kg 1 IV No serious S/E 25 Weak clinical effect IPF 14 AD-MSC /kg 3 EB No serious S/E 28 No clinical effect 8 PD-MSC IV Minor and transient acute S/E No clinical effect 29 COPD, chronic obstructive pulmonary disease; BMMC, bone marrow mononuclear cell; IV, intravenous; S/E, side effect; BM-MSC, bone marrow-derived mesenchymal stem cell; CRP, C-reactive protein; ARDS, acute respiratory distress syndrome; AD-MSC, adipose-derived mesenchymal stem cell; IPF, idiopathic pulmonary fibrosis; EB, endobronchial; PD-MSC, placenta-derived mesenchymal stem cell

4 - 이은주. 호흡기에서줄기세포치료 - 내로월 1회, 총 3회투여한뒤 12개월간추적관찰하였다. 투여와관련된부작용은뚜렷하지않은반면임상적인효능도기대만큼뚜렷하지않았다. 다른연구는총 8명의중등도이상의환자를대상으로하였으며타인의태반줄기세포를정맥주사하였다 [29]. 4명은저용량으로, 나머지 4명은고용량으로투여한뒤 6개월간추적관찰한결과, 줄기세포의투여는일시적이면서심각하지않은부작용을보였지만전반적으로는심각한문제는없었다. 하지만이연구또한임상적효과가미미하였다. 결 중간엽줄기세포가일상적인임상진료에이용되기에는넘어야할장벽들이아직많다. 여러가지장기세포로분화하는능력의발견은향후장기이식을대체할수있으리라는장밋빛미래도기대하게하였다. 그러나투여한중간엽줄기세포가곧바로상피세포로재생될것이라는예상과는달리다소회의적인후속연구들이발표되면서현재는그기대감이많이줄어든것이사실이다. 중간엽줄기세포의경우일반적으로암발생의위험이적은것으로알려져있지만장기적인연구가더필요하며, 아직은증상완화만이치료의큰부분을차지하는난치성폐질환에서보조적인요법으로고려해볼수있다. 현재까지중간엽줄기세포를이용한임상시험결과, 줄기세포치료는비교적안전한것으로나타났지만, 임상적으로뚜렷한효과는보이지못하였다. 따라서추후줄기세포이식의안정성과유효성의확립을위해대규모임상시험이필요하다. 론 중심단어 : 중간엽줄기세포 ; 치료기전 ; 임상시험 REFERENCES 1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968; 6: Yang J, Jia Z. Cell-based therapy in lung regenerative medicine. Regen Med Res 2014;2:7. 3. Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration 2013;85: Kim YI, Oh IH. Cell Biological Characteristics of Adult Stem Cells. J Korean Med Assoc 2005;48: Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8: Weiss DJ, Chambers D, Giangreco A, et al. An official American Thoracic Society workshop report: stem cells and cell therapies in lung biology and diseases. Ann Am Thorac Soc 2015;12:S79-S Sueblinvong V, Loi R, Eisenhauer PL, et al. Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells. Am J Respir Crit Care Med 2008;177: Mendez JJ, Ghaedi M, Steinbacher D, Niklason LE. Epithelial cell differentiation of human mesenchymal stromal cells in decellularized lung scaffolds. Tissue Eng Part A 2014;20: De Paepe ME, Mao Q, Ghanta S, Hovanesian V, Padbury JF. Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells. Am J Pathol 2011;178: Loi R, Beckett T, Goncz KK, Suratt BT, Weiss DJ. Limited restoration of cystic fibrosis lung epithelium in vivo with adult bone marrow-derived cells. Am J Respir Crit Care Med 2006;173: Weiss DJ, Bertoncello I, Borok Z, et al. Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc 2011;8: Schweitzer KS, Johnstone BH, Garrison J, et al. Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med 2011;183: Prockop DJ. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther 2009;17: Weiss DJ. Concise review: current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells 2014;32: Stabler CT, Lecht S, Lazarovici P, Lelkes PI. Mesenchymal stem cells for therapeutic applications in pulmonary medicine. Br Med Bull 2015;115: Rehman J, Traktuev D, Li J, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004;109: Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363: Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell 2012;10: Prockop DJ, Oh JY. Medical therapies with adult stem/pro

5 - The Korean Journal of Medicine: Vol. 89, No. 5, genitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 2012;113: Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187: Ribeiro-Paes JT, Bilaqui A, Greco OT, et al. Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis 2011;6: Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest 2013;143: Antunes MA, Laffey JG, Pelosi P, Rocco PR. Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem 2014;115: ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307: Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res 2014;15: Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183: Raghu G, Rochwerg B, Zhang Y, et al. An Official ATS/ ERS/JRS/ALAT Clinical Practice Guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med 2015;192: e3-e Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med 2013;11: Chambers DC, Enever D, Ilic N, et al. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology 2014;19:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R