附件 2： 报告人简介裴端卿 博士

中国科学院广州生物医药与健康研究院现任中国科学院广州生物医药与健康研究院院长，教

授，国家“863 计划”生物医药领域专家， 国家中长

期科技发展纲要“生殖与发育”重大研究计划专家，国家基金委杰出青年。目

前承担获国家自然科学基金重点项目，国家 973 项目，中科院知识创新基金多

项；曾担任生物化学杂志（Journal of Biological Chemistry）编委，细胞研

究杂志（Cell Research）编委，亚太干细胞网络执委，广州干细胞与再生医

学 技 术 联 盟 理 事 长 。 其 代 表 性 学 术 成 果 发 表 在 Nature ， Nature

Genetics，Cell Stem Cell，PNAS, JBC 等国际期刊上，共计 70 多篇论文，

引用达 3000 余次

研究方向：干细胞的全能性调控机制，体细胞重编程技术及机理，蛋白质在正常与癌细胞里的运送机制，EGFR 的信号传导机制与肺癌

Cell Fate Decisions during Somatic Cell Reprogramming

Duanqing Pei, Ph.D.

CAS key laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health,

Chinese Academy of Sciences, Guangzhou, China.

Somatic cell reprogramming is emerging as an ideal system for the analysis of mechanisms

involved in cell fate decisions. With clearly defined starting cells and the final iPSCs, it has

becoming possible to define the molecular events associated with the various fate changes.

We initially reported that a mesenchymal to epithelial transition or MET initiates somatic cell

reprogramming and have also identified factors critical for this starting step. Subsequently,

we refined this mechanism by demonstrating a sequential EMT-MET process for optimal

reprogramming. Therefore, the switching between mesenchymal and epithelial fates appears

to underlie the cell fate decisions during somatic cell reprogramming. We then focus on the

molecular mechanisms that specify the mesenchymal and epithelial fates and factors that

can facilitate or inhibit the transitions. We will discuss the newly identified factors for these

fate decisions. We believe that a comprehensive analysis for the EMT-MET process may help

us better understand not only reprogramming but also other cell fate changes in both normal

development and diseases.

曹旭 博士

美国约翰霍普金斯大学1986 年赴美，1991 年获得南卡罗来纳大学生

物化学博士学位。嗣后在华盛顿大学从事博士后研究。1996 年应聘到阿拉巴

马大学任人类骨细胞研究实验室主任，为该大学病理系助理教授，副教授，教

授、综合性癌症研究中心研究员、病理系分子与细胞病理研究委员会主任、病

理系教授职位遴选委员会委员，2009 年应邀至美国约翰霍普金斯大学，任骨

科 Lee Rilley 讲席教授，骨骼与肌肉研究中心主任。美国国家健康卫生中心常

务委员和项目评审专家。现为国际华人骨研究会主席，兼任纽约科学院骨髓杂

志副主编，Nature Medicine 等 16 家著名期刊的评论专家。2002 年，曹旭

教授入选中科院“百人计划” 。 2010 年被聘为“长江学者”讲座教授。曹旭

博士主要从事骨骼疾病分子病理研究，长期获得美国国立卫生研究院科研资助，

发表在 Nature Medicine 等学术杂志上的论文 90 余篇，拥有多项专利成果并

已开始进入临床实验。

Mesenchymal Stem Cells in bone remodeling and skeletal diseases

Xu Cao

Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD

To maintain skeletal integrity and homeostasis, skeleton undergoes continuous remodeling

throughout adulthood. During bone resorption, abundant factors previously buried in the

bone matrix are released into the bone marrow microenvironment, which results in

recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for

subsequent bone formation, temporally and spatially coupling bone remodeling. The bone

marrow osteogenic microenvironment that is created during osteoclast bone resorption

determines MSC fate by promoting MSC recruitment and osteoblast differentiation.

Particularly, TGFβ1 released from the bone matrix induces the migration of MSCs, whereas

IGF-1, also released from the bone matrix stimulates osteoblast differentiation of MSCs for

new bone formation. Dysregulation of TGF-β alters MSCs recruitment and their fate,

uncoupling bone remodeling and causing various skeletal disorders. Loss of site-directed

recruitment of MSCs are associated with multiple skeletal disorders. For example, Camurati-

Engelmann disease (CED) caused by mutations in TGFB1 that result in premature activation

of TGF-β1 disrupts recruitment of MSCs and uncouples bone remodeling. Uncoupled bone

remodeling also accompanies the onset of osteoarthritis. TGF-β1 is activated in subchondral

bone in response to altered mechanical loading in mouse osteoarthritis models. High levels

of active TGF-β1 induces formation of nestin+ MSC clusters via activation of ALK5-SMAD2/3.

MSCs undergoes osteoblast differentiation in these clusters, leading to formation of marrow

osteoid islets at the onset of osteoarthritis. Knockout TGFβ type II receptor specifically in

nestin+ MSCs by inducible nestin-CreER inhibits migration of nestin+ MSCs and attenuates OA

progression. Thus, modulation of TGF-β signaling in recruitment of MSCs may offer potential

therapeutic approaches for skeletal diseases.

冯新华 博士

浙江大学生命科学研究院入选第三批“千人计划国家特聘专家”，浙江大学生命科

学研究院院长，首席研究员、教授、博士生导师。 1983

年在武汉大学生物系获得学士学位；1986 年在中科院遗传学研究所获得硕士

学位；1992 年在美国 University of Maryland-College Park 获得 Ph.D.；

1993-1997 年在美国加州大学旧金山分校做博士后；1997-1999 年在美国

University of California-San Francisco 生长与发育系（现更名为组织细胞

学 系 ） 担 任 研 究 助 理 教 授 ； 1999-2003 年 在 美 国 Baylor College of

Medicine 分子与细胞生物学系、外科学系担任助理教授；2003-2007 年在美

国 Baylor College of Medicine 分子与细胞生物学系、外科学系担任副教授；

2007 年担任美国 Baylor College of Medicine 分子与细胞生物学系、外科学

系、分子生理与生物物理学系教授和 STaR 干细胞与再生医学中心研究员 、

Duncan 癌症中心研究员以及炎症生物学中心研究员；2009 年底至今，担任

浙江大学校长特别助理、生命科学研究院院长。

主要从事人类与动物细胞信号转导调控网络方面的研究，主要是研究转译后蛋

白质的修饰、生长因子信号通路上的各类调控蛋白与基因、生长因子在正常细

胞 和 肿 瘤 细 胞 中 信 号 转 导 的 机 理 。 研 究 成 果 发 表 在 如

Cell 、 Nature 、 Molecular Cell 、 Developmental Cell 、 Genes &

Development 等上发表论文 100 余篇，总被引用超过 10000 次。现担任国

家重大研究计划项目首席科学家，国家自然科学基金重大项目负责人。冯新华

博士现还为美国 JBC 杂志编委，Nature、Science 等综合期刊及 Molecular

Cell、Cancer Cell 等专业杂志的不定期评审委员。

研究方向：信号转导通路 TGF-/BMP 及蛋白质修饰机理的研究，利用分子生物学，细胞生物学以及动物模型，揭示信号转导通路在干细胞、正常器官发育以及癌症等疾病发生中的功能。Control of BMP Signaling in Mesenchymal Differentiation and Hematopoiesis

Fenfang Chen1, Yulan Zhao1, Tao Shen2, Xueyan Duan2, Xia Lin2, and Xin-Hua Feng1,2

1Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China;

2Departments of Surgery & Molecular & Cellular Biology, Baylor College of Medicine,

Houston, TX 77030, USA

BMP and related growth factors activate a broad range of cellular responses and play key

roles in the pathogenesis of many diseases especially cancer and skeletal diseases. The

activity of the BMP-initiated signaling pathway is tightly controlled, for example, through

regulation of the key downstream Smad proteins. In response to BMP, Smad1/5/8 are

phosphorylated (P-Smad1/5/8), which triggers a series of downstream signaling and gene

transcriptional events in the nucleus. To maintain proper levels of activated Smad1/5/8,

activated Smad1/5/8 in the nucleus are normally dephosphorylated and then transported

back into the cytoplasm. By using protein-protein interaction and genetic screens, we have

discovered three classes of key players: phosphatases that dephosphorylate P-Smads,

nuclear export factors that transport dephosphorylated Smads out of the nucleus, and

modulators that regulate the activity of receptors or Smads. During signal termination,

phosphatases (e.g. PPM1A, PPM1H, SCP4) physically interact with P-Smad1/5/8 and RanBP3L

specifically recognize dephosphorylated Smads for their nuclear export in a small G protein

Ran-dependent manner. As a consequence, Smad phosphatases and RanBP3L coordinately

shut down BMP-induced Smad-mediated transcriptional programs, thereby blocking BMP

signaling during mesenchymal differentiation.

周中军 博士

香港大学医学院毕业于厦门大学（学士），中国医学科学院、协和医科大

学（博士）和 瑞典 Karolinska Institute（博士）。亚洲

衰老研究学会创会主席。荣获国际蛋白酶学会 2002 年度青年研究奖，海外杰

出青年(港澳)，香港大学杰出研究学者，Croucher 基金会资深研究学者奖等荣

誉 。主要从事骨骼发育信号调控,血管发育及衰老的研究。研究方向为：1.衰老

的生物学机制及早老/老年性疾病的干预; 2.细胞外基质及基质蛋白酶在发育和

疾病过程中的信号调节。主要学术贡献

(1) 建立了MT1-MMP缺失小鼠，并揭示了MT1-MMP 在骨骼发育和血管生成

的重要性；开创性地提出 MT1-MMP 在多种信号通路调节中的主导作用,揭示了MT1-MMP 调控 Notch 信号维持造血干细胞更新及 B 细胞分化的机制；发现MT1-MMP 调控 FGF，VEGF-C 信号在骨骼发育，血管及淋巴管生成中的作用。

(2) 在核基质生物学研究首次发现核基质蛋白 Lamin A 的加工酶 Zmpste24;

阐述了及其在发育和衰老中的作用；首次提出早老症的发生与基因组不稳定相关，并多方面地阐述了 lamin A变异导致基因组不稳定的原因，揭示核基质如何影响多种组蛋白修饰酶及染色质结合蛋白的定位及功能，改变表观遗传学从而影响染色质重构，造成 DNA损伤修复缺陷，进而导致快速衰老；并针对这一缺陷通过特定的小分子化合物干预染色质重构，延缓了早老症衰老进程，为临床干预早老症以及衰老相关疾病奠定了基础。发现 Lamin A结合并可激活SIRT1，在维持干细胞自我更新中起重要作用；并首次揭 示了 Resveratrol通过促进 lamin A 与 SIRT1 的结合，从而提高 SIRT1活性，从而在分子水平阐述了 Resveratrol 激活 SIRT1 的 机 理 ，对结束长 期 以 来关于 Resveratrol 与SIRT1 的争论具有里程碑的意义。多项工作被权威综述 The Hallmarks of

Aging (Cell, 2013)引用。

核基质与染色质重构及衰老

周中军

核基质不仅存在于核膜下而且贯穿于核浆中，在维持核结构的稳定核保障核内重

要生物学活动发挥重要作用。核基质异常与人类多种疾病密切相关。如核纤层蛋白 A

突变导致包括心肌病，肌肉萎缩，脂肪发育不良和早老症在内的核纤层病变。同一蛋

白上的不同突变造成表型迥异的不同疾病，说明这些不同的病变源于与纤层蛋白相结

合的蛋白。利用 Zmpste24 基因缺失的早老症模型小鼠及人类早老症细胞，我们试图

寻找受纤层蛋白突变影响而功能受损的重要的衰老调控蛋白，并进一步探讨其在染色

质重构和衰老中的作用。 我们的研究发现 lamin A 与组蛋白修饰酶有直接的结合，

lamin A突变可导致组蛋白修饰酶与之结合能力发生显著的改变，从而造成组蛋白修

饰异常，染色质结构改变，进一步影响染色质重构和 DNA损伤修复，加速衰老。利用

遗传学和药理学恢复组蛋白修饰可恢复染色质重构缺陷和 DNA损伤修复，并能显著延

缓衰老发生，改善衰老进程及延长健康寿命。同时我们发现，lamin A是 SIRT1 和

SIRT6内源性激活剂，lamin A衰老性突变造成 SIRT1 与核基质相互作用下降，导致

SIRT1去乙酰化酶活性降低，引发干细胞衰老。白藜芦醇通过增强 lamin A 与 SIRT1

的结合，恢复 SIRT1 在核基质的定位，增强 SIRT1活性，保护干细胞自我更新，延缓

衰老。我们的研究表明， lamin A 与其结合蛋白的相互作用对调节核内重要生物学具

不可或缺的作用。

陈林 博士

第三军医大学现任第三军医大学大坪医院全军战创伤中心（实验

室）、“创伤、烧伤与复合伤国家重点实验室”所属“临床生物技术分室”、

康复医学科主任。为长江学者、国家杰青获得者、科技部重大研究计划首席科

学家，入选“新世纪百千万人才工程”、科技部重点领域创新团队“创伤修复

创新团队”负责人，享受政府特殊津贴。主要利用模式动物（小鼠、斑马鱼）

及患者资源研究骨骼发育、骨病与骨再生/康复、以及危重病器官损害发生机制

等，对 FGF 信号及骨骼发育与骨骼遗传、退行性骨病相关领域比较熟悉。先后

担任中华医学会重症医学分会、中国病生学会重症医学委员会委员、全军重症

医学分会常委、重庆市生理学会重症医学分会副主任委员、中华医学会创伤学

会创新药物与转化应用学组副组长、中国遗传学会发育遗传专业委员会、中华

医学会骨质疏松与骨矿盐疾病分会常委。已发表论文 100 余篇，SCI他引

2500 余次。

FGF信号在骨骼发育及骨骼遗传疾病及退行骨病中作用与机制研究

陈林

成纤维细胞生长因子（FGF）信号有 22个配体（FGF）成员、4个受体（FGFR1-

4），属于酪氨酸激酶受体家族。FGF 信号与人类骨骼发育及稳态维持关系密切，

FGFR1、2、3、FGF9、10、23 等突变后可导致侏儒、囟门早闭、关节融合、腭裂、

磷代谢异常等多种骨骼遗传病，此外，FGF 信号还在骨、关节稳态维持中起重要作用。

为研究 FGF 信号在骨骼发育及相关骨骼遗传、退行性疾病中的作用，模式小鼠被广泛

应用。我们将以模式小鼠为重点，介绍 FGF 信号与骨骼发育及相关骨病的关系，并展

望今后的研究方向。

孙凌云 博士

南京大学主任医师/教授，南京大学博士生导师，南京大学

医学院附属鼓楼医院免疫科主任，南京大学风湿免疫研究所所长。曾任全国风

湿免疫学会副主任委员和江苏省风湿病学会主任委员。现任全国医师学会风湿

免疫专科分会副会长、江苏省风湿病学会候任主任委员。1998 年率先在亚洲

开展红斑狼疮造血干细胞移植。2007 年在国际率先开展异体骨髓间充质干细

胞移植治疗红斑狼疮、硬皮病、类风湿关节炎等 700例，相关研究曾 36 次在

美国风湿病学、欧洲风湿病学年会和欧洲骨髓移植大会等国际会议发言。承担

国家自然基金中美国际重大项目、国家自然基金重大研究计划和中英干细胞合

作研 究 项 目 等 20 项 。 在 Cell Stem Cell 、 J Exp Med 、 Nature Rev

Rheum、Blood、Gut、Stem Cells、J Immunol、Arthritis Rheum、Ann

Rheum Dis 等发表论文 320 余篇，其中 SCI 论文 102 篇，任 International

Journal of Rheumatic Diseases 杂志副主编，主编专著 6部，参编 12部，

获江苏省科技进步一等奖、中华医学科技奖二等奖和教育部科技进步二等奖等

18 项。2002 年享受国务院津贴，2011 年评为十一五江苏省优秀医学重点人

才，十二五江苏省重点学科带头人、江苏省十佳健康卫士、江苏省和卫生部有

突出贡献中青年专家、全国卫生系统先进工作者、南京市劳模、南京十大科技

之星、南京科技功臣、江苏省先进科技工作者。

Mesenchymal stem cell therapy in autoimmune diseases

Lingyun Sun

The Drum Tower Hospital of Nanjing University Medical School

Autoimmune diseases (AD) are a group of heterogeneous disorders including systemic lupus

erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA),

scleroderma (SSc), multiple sclerosis (MS) and so on. The steroids and immunosuppressants

have been mainly used to treat the AD. However, about 1/4 of patients were still resistant to

these conventional therapies even with biologic agents. Over the past two decades, more

than 2000 patients worldwide have been treated by hematopoietic stem cell transplantation

(HSCT) for the AD with good response. Recently, mesenchymal stem cell transplantation

(MSCT) has been explored in both AD models and humans with encouraging results and

safety. There are over 1000 patients with AD especially in lupus have been treated with

allogeneic MSCT in China from 2007 to 2014 though the majority of patients are from single-

centre trials without randomized controlling. The efficacy rate of MSCT for lupus is about

60% including complete and partial remission with 20%-30% relapse in one year follow-up.

Furthermore, the transplantation related mortality of allogeneic MSCT is 0% due to without

myeloablative cyclophosphamide (CTX) precondition. A plethora of different mechanisms

involved in therapeutic effect in a variety of autoimmune diseases suggesting that

mesenchymal stem cell play different immunoregulations and repaires when they arrived in

different inflammatory environment.

Cheng-Ming. Chuong, M.D., Ph.D.

Dr. Cheng-Ming Chuong received his M.D. from

Taiwan University in 1978. He then obtained his

Ph.D. from The Rockefeller University in 1983. Later

he moved to the University of Southern California in

1987 and work on the development and regeneration of feather, tooth, and hairs. He

is currently a professor of pathology and also serves as the Chair of Graduate

Committee in Department of Pathology. Dr. Chuong directs the Laboratory of Tissue

Development and Engineering (http://www-hsc.usc.edu/~cmchuong/

cmchuong@usc.edu) in the Department of Pathology, USC. The laboratory is manly

supported by National Institute of Health and studies how stem cells are guided to

form special tissues and organs of specific size and shape.

Dr. Chuong has received many honors including the award for creativity in research

by USC. In 2008, he was elected to the prestigious Academia Sinica, the National

Academy equivalent of Taiwan. In 2014, he was elected as a fellow of American

Association for the Advancement of Science for “Distinguished contribution to

advance new understanding in the development, regeneration and evolution of

patterns in ectodermal organs”. His work on Evo-Devo of feathers contributes to new

understanding in the “The Birth of Birds” which was chosen by Science as one of the

10 major breakthroughs in 2014.

Using the ectoderm as a model, his laboratory learned from nature how to mold

stem cells into different ectodermal organs during development, evolution and stem

cell engineering. He has promoted the concept of "topobiology" which is crucial for

guiding epidermal stem cells into proper architectures. He demonstrated how the

process can guide stem cells to the multiple forms of ectodermal organs.

Dr. Chuong has published more than 210 papers on the biology of integuments in top

journals, including multiple research papers and commentaries in Nature, Science,

Cell. He publishes two books (Molecular Basis of Epithelial Appendage

Morphogenesis; Fossil Birds of China) and two journal special issues (Development

and Evolution of Amniote Integuments; Pattern Formation). He is an associate editor

of J. Investigative Dermatology, Expt. Dematology and on the editorial board of

Developmental Biology, Genesis, J. Expt. Zoology.

He wrote chapters for textbooks on stem cell biology and regenerative medicine in

English and in Chinese. He is frequently interviewed by the media for his work in

stem cell biology and evolution and development of feathers and other integument

organs. Interviews have appeared in LA times, BBC, Scientific American, Smithonian

magazine, NPR, Science Daily News, Business week, Chinese Daily news, Fox news,

etc.

In Taiwan, he works as honorary director for Center for Developmental Biology and

Regenerative Medicine of National Taiwan University, Integrative Stem Cell Center of

China Medical University, International laboratory of Would Repair and Regeneration

of Natilonal Cheng Kung University (iWRR), and Integrative Evolutionary Galliform

Genomics (iEGG) Center of National Chung Hsing University.

Skin organs: regeneration, engineering and evolution

Cheng Ming Chuong, M.D., Ph.D.

Department of Pathology, University of Southern California, Los Angeles, CA 90033

cmchuong@usc.edu http://www-hsc.usc.edu/~cmchuong

Coordinated organ behavior is crucial for an effective response to environmental

stimuli. Here we show that, in a field of resting telogen follicles, plucking a few properly

arranged hairs can trigger the regeneration of up to 5 times more neighboring, unplucked

resting hairs. Such collective regeneration is threshold dependent and provides an example

of quorum sensing at the organ-level., a form of social behavior through which populations

make collective decisions. Through mathematical modeling of experimental data, the range

of action of the quorum signal was estimated to be on the order of 1 mm, greater than what

is usually expected from diffusible signaling molecules. Using a combination of molecular

profiling, in situ expression, and analyses with transgenic mice, we discovered a two-step

mechanism. The release of distressor signaling from injured hair keratinocytes of plucked

follicles leads to the recruitment of TNF- secreting macrophages, which accumulate and

signal to both plucked and unplucked follicles. Thus a chemical cytokine is combined with a

mobile cellular vector to mediate the long distance spreading of the quorum signaling. By

topological positioning of plucked and unplucked follicles (what matters is the density and

the shape of the plucked field, not the absolute number of plucked follicles), we can enhance

the spreading of quorum sensing signals and maximize the activation of stem cells in the hair

follicle population. Thus, by coupling immune response with regeneration, this mechanism

allows skin to respond predictively to distress, disregarding mild injury, while meeting

stronger injury with full-scale cooperative activation of stem cells. We contemplate such

organ level quorum sensing behavior principle to be present in the regeneration of tissue

and organs beyond the skin. In a larger scale, the external environment can also affect hair

growth during the life time of an animal. In an even larger evolutionary scale, ecological

environment can shape animal species.

In Dec 2014, “the birth of birds” was chosen as one of the 10 major breakthroughs by

Science. In essence, the evolution of diverse forms of hair and feather skin appendages is not

possible without stem cells based regeneration. This is an acknowledgement to our

integrative study on how feathered dinosaurs are transformed into birds. As the first step of

feather evolution, integument was compartmentalized into multi-units, and each unit has its

own stem cells and cycle independently. With thousands of units (feather follicles) on the

body surface, these feathers can start to evolve regional specific feathers. They include

downy feathers in the body, flight feathers in the wing, and crown and tail feathers for

insulation, flight, and communication respectively. Therefore periodic patterning is an

effective design that made all these possible. We are not only look at the regeneration of a

single follicle, but the regenerative behavior of a follicle population, with emergence of new

possibilities.

Chuong CM, Randall VA, Widelitz RB, Wu P, Jiang TX. 2012. Physiological regeneration of skin

appendages. Physiology. 27:61-72.

Chen CC, Wang L, Plikus MV, Jiang TX, Murray PJ, Ramos R, Guerrero-Juarez CF, Hughes MW,

Lee OK, Shi ST, Widelitz RB, Lander AD, Chuong CM. (2015). Organ-Level Quorum Sensing

Directs Regeneration In Hair Stem Cell Populations. Cell;161:277-90.

Lee L, Jiang TX, Garner W, Chuong CM. 2011. A simplified procedure to reconstitute hair

producing skin. Tissue Engineering 17:391-400.

Lin SJ, Foley J, Jiang TX, Yeh CY, Wu P, Foley A, Yeh CM, Huang YC, Cheng HC, Chen CF, Reeder

B, Jee SH, Widelitz RB, Chuong CM. 2013. Topology of feather melanocyte progenitor niche

allows complex pigment patterns to emerge. Science. 340:1442-1445.

Xu X; Zhou Z, Dudley R, Mackem S,

Chuong CM, Erickson GM, Varricchio DJ,

2014, An Integrative Approach to

Understanding Bird Origins. Science,

346: 1253293. Songtao Shi Ph.D.

Songtao Shi, D.D.S., Ph.D., is

Professor and Department Chair at the University Of Pennsylvania School Of Dental

Medicine. Dr. Shi received his D.D.S. degree and certificate in Pediatric Dentistry from

the Peking University School of Stomatology and Ph.D. in Craniofacial Biology from

the University of Southern California. Prior to joining the faculty at the University of

Pennsylvania, he served as a Principal Investigator and Clinical Fellow for nine years

at the National Institute of Dental and Craniofacial Research and a professor for more

than eight years at the University of Southern California.

His research program focuses on understanding mechanism of mesenchymal stem

cell (MSC)-associated diseases, developing new experimental disease models, and

exploring feasibility of translating these bench discoveries to clinical therapies. His

group and his collaborators were the first to identify dental pulp stem cells, baby

tooth stem cells, periodontal ligament stem cells, root apical papilla stem cells,

tendon stem cells, gingiva stem cells, sclera MSCs, and benign tumor MSCs from

keloid. These novel and landmark discoveries have opened opportunity for scientists

to investigate oral tissues derived stem cells and their use for tissue engineering,

disease modeling, and clinical treatment.

In translational study, Dr. Shi’s team has used these stem cells to regenerate a variety

of tissues, including dentin, pulp, periodontal ligament, tendon, bone, bio-root in

preclinical animal models. Dr. Shi and his collaborators were the first to use MSCs to

treat systemic lupus erythematosus (SLE), and regenerate periodontal and pulp

tissues in patients. Additionally, Dr. Shi and his collaborators were the first to

generate bisphosphonate-related osteonecrosis of the jaw-like disease (BRONJ) and

keloid disease models in mice and swine.

To understand mechanisms of MSC-based therapies, Dr. Shi’s team was the first to

reveal that recipient immune cells regulated cell-based bone regeneration.

Additionally, Dr. Shi and his collaborators discovered that the interplay between the

donor cells and recipient T cells determined MSC-mediated immunotherapeutic

effect in human and mouse model. Dr. Shi, as corresponding author, has published

more than 160 peer-reviewed articles in a variety of high-impact scientific journals,

of which he served as the corresponding author in Nat Medicine, Cell Stem Cell,

Immunity, Lancet, J Clin Invest, Nat Biotechnol, Journal of Experimental Medicine,

Proc Natl Acad Sci U S A, Cell Research, Blood, J Bone Miner Res, Stem Cells, and J

Dent Res. According to the google scholar, Dr. Shi’s publication has been cited over

23,300 times (http://scholar.google.com/citations?user=q1HfzhoAAAAJ&hl=en). Dr.

Shi’s research is supported by NIH grants and funding from California Institute of

Regenerative Medicine.

Clinically, Dr. Shi hold Dental Licensure of State of California and had experience

working at NIH hospital and private practice section in USA. This background makes

Dr. Shi a highly qualified translational researcher to study orofacial disorders and

explore cure for orofacial diseases. Dr. Shi has served on several local and national

committees and boards including Scientific Editor for the PLoS ONE and Associate

Editor for Oral Diseases. He is recipient of the 2013 IADR Distinguished Scientist

Award for Pulp Biology & Regeneration. His service has also included: Scientific

Advisory Boards for the Journal of Endodontics, the Scientific Committee of Chinese

Stomatological Association, and the Scientific Committee of Chinese Military

Stomatology Research Institute. Dr. Shi is Changjing Scholar in the Fourth Military

Medical University, Distinguished Visiting Professor in Tongji University, Visiting

Professor in XiangYa School of Medicine & Stomatology, Central South University

(CSU), and distinguished visiting professor in Dankook University, Korea.

Mesenchymal Stem Cells: Diseases and Cure

Songtao Shi, DDS, PhD

University of Pennsylvania

Mesenchymal stem cells (MSCs) are a population of hierarchical postnatal stem cells with the

potential to multiple differentiations and thus serve as a promising cell source for

regenerative medicine in terms of forming mineralized tissues to replace damaged and

diseased tissues. MSCs have been successfully used for mineralized and soft tissue

regeneration in animal models and clinics. ALSO, MSCs display profound immunomodulatory

properties by inhibiting proliferation and function of several major immune cells, such as

dendritic cells, T and B lymphocytes, and natural killer (NK) cells. In fact, MSC-based therapy

has been successfully applied in various human diseases, including graft versus host disease

(GvHD), systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune

encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. We found that

systemic infusion of MSCs induced transient T-cell apoptosis via the Fas ligand (FasL)-

dependent Fas pathway and could ameliorate disease phenotypes in fibrillin-1 mutated

systemic sclerosis (SS) and dextran sulfate sodium-induced experimental colitis. Mechanistic

analysis revealed that Fas-regulated monocyte chemotactic protein 1 (MCP-1) secretion by

MSCs recruited T-cells for FasL-mediated apoptosis. The apoptotic T-cells subsequently

triggered macrophages to produce high levels of TGF-β which in turn led to the upregulation

of Tregs and, ultimately, to immune tolerance. These data therefore demonstrate a

previously unrecognized mechanism underlying MSC-based immunotherapy involving

coupling via Fas/FasL to induce T-cell apoptosis.

Although stem cell-based regenerative medicine is a promising approach for functional tissue

reconstruction, the role of immune responses in the cell-based tissue regeneration remains

unclear. We showed that pro-inflammatory T cells in the recipients inhibited bone marrow

MSC (BMMSC)-mediated bone formation via T helper 1 (Th1) cytokine interferon IFN-γ

induced down-regulation of runt-related transcription factor 2 (Runx-2) pathway and tumor

necrosis factor TNF-α regulated BMMSC apoptosis. We revealed that TNF-α converted IFN-γ-

activated non-apoptotic Fas to a caspase 3/8-associated apoptotic signaling in BMMSCs

through inhibition of nuclear factor kappa B (NF-κB), resulting in BMMSC apoptosis.

Conversely, reduction of IFN-γ and TNF-αlevels at the implantation sites by systemic infusion

of Foxp3+ regulatory T cells (T-regs) markedly improved BMMSC-based bone regeneration

and calvarial defect repair in C57BL6 mice. For potential pharmacologic intervention, we

showed that local administration of aspirin reduced levels of IFN-γ and TNF-α at the

implantation site and significantly improved BMMSC-based calvarial defect repair. These data

collectively uncover a previously unrecognized role of recipient T cells in BMMSC-based

tissue engineering and suggest a practical approach for enhancing bone regeneration by

pharmacological control of local cytokines.