• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제47권2호
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• pp.65-75
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• 2021

Medication-related osteonecrosis of the jaw (MRONJ) has recently associated to the increase in antiresorptive and anti-angiogenic drugs prescriptions in the treatment of oncologic and osteoporotic patients. The physiopathogenesis of MRONJ remains unclear and available treatments are unsatisfactory. Newer pharmacological treatments have shown good results, but are not curative and could have major side effects. At the same time as pharmacological treatments, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality for tissue regeneration and repair. MSCs are multipotential non-hematopoietic progenitor cells capable to differentiating into multiple lineages of the mesenchyme. Bone marrow MSCs can differentiate into osteogenic cells and display immunological properties and secrete paracrine anti-inflammatory factors in damaged tissues. The immunomodulatory, reparative, and anti-inflammatory properties of bone marrow MSCs have been tested in a variety of animal models of MRONJ and applied in specific clinical settings. The aim of this review is to discuss critically the immunogenicity and immunomodulatory properties of MSCs, both in vitro and in vivo, the possible underlying mechanisms of their effects, and their potential clinical use as modulators of immune responses in MRONJ, and to identify clinical safety and recommendations for future research.

• 한국발생생물학회:학술대회논문집
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• 한국발생생물학회 2003년도 제3회 국제심포지움 및 학술대회
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• pp.71-71
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• 2003

Human umbilical cord blood cells(HUCBC) are rich in mesenchymal progenitor cells, endothelial cell precursors and hematopoietic cells. HUCBC have been used as a source of transplantable stem and progenitor cells. However, little is known about survival and development of HUCBC transplantation in the CNS. Estrogen has a neuroprotective potential against oxidative stress-induced cell death so has an effect on reducing infarct size of ischemic brain. We investigated the potential use of HUCBC as donor cells and tested whether estrogen mediates intravenously infused HUCBC enter and survive in ischemic brain. PKH26 labeled mononuclear fraction of HUCBC were injected into the tail vein of ischemic OVX rat brain with or without $17\beta$-estradiol valerate(EV). Under fluorescence microscopy, labeled cells were observed in the brain section. Significantly more cells were found in the ischemic brain than in the non-ischemic brain. HUCBC transplanted into ischemic brain could migrate and survive. Some of cells have shown neuronal like cells in hippocampus, striatum and cortex tissues. These result suggest that estrogen reduces ischemic damage and increases the migration of human umbilical cord blood cells. This Study was supported by the Korea Science and Engineering Foundation(KOSEF) though the Biohealth Products Research Center(BPRC), Inje University, Korea.

• IMMUNE NETWORK
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• 제3권1호
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• pp.8-15
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• 2003

Background: CD30 is a member of TNF receptor family and expressed on lymphocytes and other hematopoietic cells following activation as well as Hodgkin and Reed-Sternberg cells in Hodgkin's lymphoma. In this study, CD30-mediated regulation of cell adhesion molecule expression on normal activated mouse T cells was investigated. Methods: Mouse T cells were activated with anti-CD3 antibody for induction of CD30, which was cross-linked by immobilized anti-CD30 antibody. Results: High level of CD30 expression on T cells was observed on day 5, but only little on day 3 even under culture condition resulting in an identical T cell proliferation, indicating that CD30 expression requires a prolonged stimulation up to 5 days. Cross-linking of CD30 alone altered neither proliferation nor apoptosis of normal activated T cells. Instead, CD30 appeared to promote cell adherence to culture substrate, and considerably upregulated ICAM-1 and, to a lesser extent, ICAM-2 expression on activated T cells, whereas CD2 and CD18 (LFA-1) expression was not affected. None of cytokines known as main regulators of ICAM-1 expression on tissue cells (IL 4, $IFN{\gamma}$ and $IFN{\alpha}$) enhanced ICAM-1 expression in the absence of CD30 signals. On the other hand, addition of $NF-{\kappa}B$ inhibitor, PDTC (0.1 mM) completely abrogated the CD30-mediated upregulation of ICAM-1 expression, but not CD2 and ICAM-2 expression. Conclusion: This results support that CD30 upregulates ICAM-1 expression of T cell and such regulation is not mediated by higher cytokine production but $NF-{\kappa}B$ activation. Therefore, CD30 may play important roles in T-T or T-B cell interaction through regulation of ICAM-1, and -2 expression.

• Archives of Plastic Surgery
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• 제35권3호
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• pp.229-234
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• 2008

Purpose: There are some reports presenting that peripheral blood contain circulating hematopoietic cells as well as, in significantly smaller quantities, mesenchymal stem cells. The purposes of this study is to isolate and characterize circulating mesenchymal progenitor cells with osteogenic potential from human peripheral blood. Methods: Human buffycoat containing mononuclear cells was harvested from peripheral blood of normal persons and isolated using a density gradient centrifugation and serially subcultured in osteogenic media for 1-4 weeks. The proliferation capability, phase-contrast microscopy, transmission electron microscopy, immunophenotype FACS analysis, Alizarin red staining and RT-PCR assays for osteogenic differentiation potential were performed. Results: The phenotype of cultured cells changed from small round or cuboidal cells at passage 1 into large spindle-shaped fibroblastic morphology cells at passage 4. Surface marker expressed CD14, but did not express CD34, CD80, CD83. Strong positive staining was observed for Alizarin reds in osteogenic medium on day 14, Using RT-PCR, the mRNA levels of bone- specific genes, such as ALP, c-bfa-1 and osteocalcin were detected. Conclusion: A new subset of peripheral blood derived progenitor cells described here has the ability to proliferate and differentiate into osteogenic cell lineages in vitro, and to be candidate for regenerative therapy.

• Korean Chemical Engineering Research
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• 제44권1호
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• pp.73-80
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• 2006

본 연구에서는 제대혈 유래의 조혈줄기세포를 효과적으로 배양하기 위한 선행 연구로서 세포 배양 환경에 따른 조혈줄기세포 증식능의 변화를 관찰하였다. 제대혈의 단핵구 세포에서 분리한 $CD34^+$ 세포를 성장인자 조성-I(이하, coc-I) (EPO, GM-CSF, SCF, IL-3) 및 성장인자 조성-II(이하, coc-II) (TPO, G-CSF, SCF, IL-6, Flt3/Flk-2 ligand)가 포함되어 있는 IMDM(Iscove's modified Dulbecco's medium) 및 무혈청 배지(serum free media, SFM)에서 배양하였으며, 우태아혈청(FBS)의 첨가 영향, 2차원 및 3차원 배양 후 각 조건에서의 세포 증식 및 콜로니 형성능을 비교하였다. 일반적으로 coc-I에서의 세포 증식 및 콜로니 증식이 coc-II에서보다 높았다. 3차원 배양(methocult)에서는 가장 높은 세포 증식($2,258{\pm}456$배)을 나타냈으며, 같은 조성의 2차원 배양(IMDM + coc-I + FBS)에서는 가장 높은 콜로니 증식(BFU-E: $652{\pm}19$, CFU-GM: $520{\pm}58$, CFU-GEMM: $339{\pm}100$배)이 나타났다. 배지를 기준으로 보면, coc-II 조성에 우태아혈청이 포함되지 않은 경우를 제외한 모든 경우에서 세포 증식 및 콜로니 증식이 무혈청 배지에서보다 IMDM에서 높았다. 결론적으로, 모든 배양 조건 중에서 'IMDM + coc-I + FBS' 및 'IMDM + coc-I'에서 가장 좋은 콜로니 증식을 보였으며, 우태아혈청의 첨가 및 2차원 배양 조건이 콜로니 증식에 더 효과적인 것으로 확인되었다. 본 연구 결과는 앞으로 조혈줄기세포의 체외 증식에 필요한 공정개발이나 생물반응기 설계에 유용한 정보를 제공할 수 있을 것으로 사료된다.

• 한국식품과학회지
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• 제30권4호
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• pp.888-894
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• 1998

한방 보혈제의 기본처방인 사물탕과 보기제의 기본 처방인 사군자탕의 방사선 조사 마우스에서의 방사선 방호 효과를 소장움 생존(고선량 방사선, 12 Gy), 조혈세포 생존(중간선량 방사선, 6.5 Gy), apoptosis 형성(저선량 방사선, 2 Gy) 실험법을 적용하여 관찰하였다. 방사선조사 전 사물탕투여군(경구투여: 음수 mL당 2 mg씩 7일간, 복강내주사: 마리당 1 mg씩 방사선 조사 24시간 전)에서 소장움의 생존이 증가되었으며 (방사선대조군: $38.48{\pm}4.34$, 복강내 주사군: $77.98{\pm}16.11$, P<0.005), endogenous spleen colony의 형성도 높게 나타났고(방사선대조군: $3.5{\pm}4$, 경구투여군: $10.7{\pm}7.730$, 복강내주사군: $8.667{\pm}5.244$, P<0.05), 소장움에서의 apoptotic cell의 발생율은 억제되었다(방사선대조군: $5.111{\pm}0.529$, 복강내주사군 $3.919{\pm}0.214$, P<0.01). 사군자탕 병행투여군에서는 이상의 실험에서 통계적으로 유의성 있는 효과는 없었다. 이상의 결과는 사물탕이 방사선방호 식품으로 활용될 수 있는 가능성을 제시하였으며, 각 구성약재 및 성분의 효과에 대한 연구가 계속되어야 할 것이다.

• IMMUNE NETWORK
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• 제3권2호
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• pp.150-155
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• 2003

Background: We investigated the effect of donor marrow T cell depletion, administration of FK506, cyclosporin A (CSA), and 3-deazaadenosine (DZA) on graft versus host disease (GVHD) after allogeneic murine hematopoietic stem cell transplantation (HSCT). Methods: We used 4 to 6 week old Balb/c ($H-2^d$, recipient), and C3H/He ($H-2^k$, donor) mice. Total body irradiated recipients received $1{\times}10^7$ bone marrow cells (BM) and $0.5{\times}10^7$ splenocytes of donor under FK506 (36 mg/kg/day), CSA (5 mg/kg/day, 20 mg/kg/day), and DZA (45 mg/kg/day), which were injected intraperitoneally from day 1 to day 14 daily and then three times a week for another 2 weeks. To prevent the GVHD, irradiated Balb/c mice were transplanted with $1{\times}10^7$ rotor-off (R/O) cells of donor BM. The severity of GVHD was assessed daily by clinical scoring method. Results: All experimental groups were well grafted after HSCT. Mice in experimental group showed higher GVHD score and more rapid progression of GVHD than the mice with R/O cells (R/O group) (p<0.01). There were relatively low GVHD scores and slow progressions in FK506 and low dose CSAgroups than high dose CSA group (p<0.01). The survival was better in FK506 group than low dose CSA group. All mice treated with CSA died within 12 days after HSCT. The GVHD score in DZA group was low and slow in comparison with control group (p<0.05), but severity and progression were similar with low dose CSA group (p=0.11). All mice without immunosuppressive treatment died within 8 days, but all survived in R/O group (p<0.01). Survival in low dose CSA group was longer than in control group (p<0.05), but in high dose CSA group, survival was similar to control group. The survival benefit in DZA group was similar with low dose CSA group. FK506 group has the best survival benefit than other groups (p<0.01), comparable with R/O group (p=0.18), although probability of survival was 60%. Conclusion: We developed lethal GVHD model after allogeneic murine HSCT. In this model, immunosuppressive agents showed survival benefits in prevention of GVHD. DZA showed similar survival benefits to low dose CSA. We propose that DZA can be used as a new immunosuppressive agent to prevent GVHD after allogeneic HSCT.

• Clinical and Experimental Pediatrics
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• 제49권2호
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• pp.173-180
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• 2006

목 적 : CMV 감염은 여전히 조혈모세포 이식 후 가장 중요한 감염 중 하나로 이환율과 사망률의 주요 원인이다. 조혈모세포 이식 후 CMV 감염 발생에 대한 위험인자의 분석 및 CMV pp65 항원혈증에 입각한 선제치료의 효과와 질환의 경과를 평가하고자 본 연구를 시행하였다. 방 법 : 1998년 10월부터 2003년 12월까지 가톨릭대학교 성모병원 소아과에서 이식을 시행받은 환아를 대상으로 하였다. pp66항원을 이용한 항원혈증검사를 토대로 혈연간 이식 환아의 경우 CMV 항원 양성세포가 5개 이상 발견된 경우, 비혈연간 이식 환아의 경우는 CMV 항원 양성세포가 하나라도 발견된 경우 ganciclovir 선제치료를 시작하였다. 결 과 : CMV 항원혈증은 대상 환아 213명 중 88명(41.3%)에서 관찰되었고, 각각 비혈연간 골수이식(62.5%), 비혈연간 제대혈이식(36.8%), HLA-일치 혈연간 이식(25.3%)이었다. 이식유형에 따른 CMV 항원혈증 발생확률은 비혈연간 골수이식($62.5{\pm}5.4%$)이 비혈연간 제대혈이식($36.8{\pm}7.8%$) 또는 HLA-일치 혈연간 이식($25.3{\pm}4.5%$)보다 통계적으로 유의하게 높았다. 단변량 분석에 의하면 비혈연간 이식, 이식 시 환자 연령(5세 이상), 이식 전 환자의 CMV-IgG, 전처치로 전신방사선조사의 사용 및 2도 이상의 급성 이식편대 숙주병의 발생이 CMV 항원혈증 발생의 위험인자이었다. 다변량분석에 의하면 비혈연간 이식, 이식전 환자의 CMV-IgG 양성상태 및 2도 이상의 급성 이식편대 숙주병의 발생이 독립적인 위험인자이었다. 이식환자 213명 중 7례(3.3%)에서 CMV 질환이 발생하였다(고항원혈증에서 6례 발생). 결 론 : 소아 조혈모세포 이식에 있어서 CMV 감염의 위험인자는 이식 전 환자의 CMV 혈청학적 상태, 조혈모세포 공급원, 급성 이식편대 숙주병이었으며, CMV 항원혈증에 입각한 ganciclovir 선제치료는 CMV 질환의 발생을 예방하는데 효과적이었다.

• 한국식품영양과학회지
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• 제34권5호
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• pp.605-612
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• 2005

방사선 생체손상의 방어 및 회복에 높은 효과를 나타내는 생약조합을 도출하고자 하였다. 이전의 연구에서 6가지 기존 보기${\cdot}$보혈 한약처방제의 방어효과를 검색하여, 재생조직 방어에는 사물탕 및 보중익기탕이, 조혈계 방어에는 보중익기탕 및 사물탕이 높은 효과를 나타내는 것으로 보고된바 있다. 본 연구에서 기존 6가지 처방제의 면역 세포 활성화 효과를 검색한 결과 모두 높은 효과를 나타내지 않았다. 따라서, 처방제의 구성 생약 각각의 효과검증 결과를 바탕으로 재생조직 방어, 조혈계 방어, 면역조혈계 회복 증진 효과를 동시에 높게 나타내는 새로운 생약조합을 도출하였다. 즉, 당귀, 천궁, 백작약을 동일 무게 비율로 혼합하여 열수 추출한 것을 새로운 생약복합물 HIM-I으로 개발하였으며 그 효과를 검정하였다. 본 생약복합물 HIM-I은 면역 세포 활성화에서는 상기한 한약처방제보다 월등하게 높은 효과를 보였으며, 조혈계 촉진효과도 높은 것으로 나타났다. 또한, 재생조직 및 면역조혈계의 방어 측면에서도 사물탕 및 보중익기탕과 같은 높은 효과를 보였다. 한편, 시험관 내에서 높은 항산화 효과를 나타내는 것으로 보아, 이 항산화 작용이 방사선 손상에 대한 방어효과의 작용기전 중의 하나로 생각되었다. 이상의 결과로 보아, 생약복합물 HIM-I은 재생조직방어, 조혈계 방어, 면역조혈계 회복 증진 효과를 동시에 나타냄으로써 방사선뿐만 아니라 여러 가지 원인으로부터 생체를 방호하고 회복시키는데 유용할 것으로 생각된다.

• International Journal of Oral Biology
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• 제32권1호
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• pp.1-5
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• 2007

Receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL) induces osteoclast formation from hematopoietic cells via up-regulation of positive regulators, including $NF-{\kappa}B$, c-Fos, microphthalmia transcription factor (Mitf), PU.1, and nuclear factor of activated T cells (NFAT) c1. In addition to the positive regulation by these transcription factors, RANKL appears to regulate negative regulators such as MafB and inhibitors of differentiation (Ids). Ids and MafB are abundantly expressed in osteoclast precursors, bone marrowderived monocyte/macrophage lineage cells (BMMs). Expression levels of these genes are significantly reduced by RANKL during osteoclastogenesis. Overexpression of these genes in BMMs inhibits the formation of tartarate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts by down-regulation of NFATc1 and osteoclast-associated receptor (OSCAR), which are important for osteoclast differentiation. Furthermore, reduced expression of these genes enhances osteoclastogenesis and increases expression of NFATc1 and OSCAR. Taken together, RANKL induces osteoclastogenesis via up-regulation of positive regulators as well as down-regulation of negative regulators.