胰腺干细胞研究的现状与展望
洪天配,北京大学第三医院内分泌科, 北京大学干细胞研究中心, 北京大学糖尿病中心 北京市 100083
洪天配, 男, 1963-07-28生, 博士, 教授, 主任医师, 博士生导师, 福建省南安市人, 汉族.1985年毕业于福建医科大学医学系, 获医学学士学位, 1991年毕业于北京医科大学, 获医学博士学位, 1997-09-06至1999-10-07在丹麦Steno糖尿病中心从事客座研究.主要从事胰岛损伤与功能重建的研究, 参与编写专著和教材4部, 发表论文及综述50篇.现任中华医学会糖尿病分会青年委员、北京糖尿病防治协会理事、北京医学会糖尿病专业委员会委员、中华糖尿病杂志编委、世界华人消化杂志编委等.
国家自然科学基金项目, No. 30040022, No. 30170443
, http://www.100md.com
“211工程”建设项目人体干细胞工程学学科群项目
美国纽约中华医学基金专项人才基金项目
国家973项目子课题, No. 2001CB510105
项目负责人: 洪天配, 100083, 北京市花园北路49号, 北京大学第三医院内分泌科. tpho66@bjmu.edu.cn
电话: 010-62017691 传真: 010-62017700
收稿日期: 2005-01-10 接受日期: 2005-01-19
摘要干细胞根据其来源的不同，可分为胚胎干(ES)细胞和成体干细胞.临床胰岛移植的成功引发了胰岛组织来源不足的巨大压力，从而促使胰腺干细胞研究成为当前的热门课题.理论上，胰腺干细胞可能存在于胰腺组织(如导管上皮)中或由ES细胞分化而来，胰岛细胞还可能来源于其他组织干细胞的横向分化.有关成年胰腺组织中是否存在胰腺干细胞、巢蛋白是否为胰腺干细胞的特异性标志物、巢蛋白阳性细胞在体外是否能真正诱导分化为胰岛素分泌细胞等焦点问题，目前存在激烈的争论.晚近，已从胰腺组织中成功建立了单克隆的多能胰腺干细胞，并在单细胞水平上对胰腺干细胞的体外分化规律进行了初步的描述.同时，多数学者认为巢蛋白不是胰腺干细胞高度特异性的一种标志物，单独应用巢蛋白不足以作为胰腺干细胞的鉴定标准.此外，在有外源性胰岛素存在的培养条件下，单独检测胰岛素的含量和释放反应对于干细胞分化而来的胰岛素产生细胞的鉴定不够可靠，可能出现假阳性结果，建议联合采用多种不同的检测方法.尽管胰腺干细胞研究取得的成果仅仅是初步的，但随着干细胞研究的深入发展和技术突破，必将为糖尿病治疗学领域开辟一片崭新的天地.
, http://www.100md.com
关键词:胰腺干细胞; 糖尿病; 胰岛素
洪天配. 胰腺干细胞研究的现状与展望. 世界华人消化杂志 2005;13(3):286-289
Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the
development and progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med 1993;329:977-986
2 UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared
, http://www.100md.com
with conventional treatment and risk of complications in patients with type 2 diabetes(UKPDS 33). Lancet
1998;352:837-853
3 Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in
seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.
N Engl J Med 2000;343:230-238
, 百拇医药
4 Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of insulin-dependent diabetes using
islets generated in vitro from pancreatic stem cells. Nat Med 2000;6:278-282
5 Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF. Multipotential
nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine,and hepatic phenotypes. Diabetes 2001;50:521-533
, 百拇医药
6 Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell
lines derived from human blastocytes. Science 1998;282:1145-1147
7 Hwang WS, Ryu YJ, Park JH, Park ES, Lee EG, Koo JM, Jeon HY, Lee BC, Kang SK, Kim SJ, Ahn C, Hwang JH,Park KY, Cibelli JB, Moon SY. Evidence of a pluripotent human embryonic stem cell line derived from a cloned
, 百拇医药 blastocyst. Science 2004;303:1669-1674
8 Soria B, Skoudy A, Martin F. From stem cell to beta cells: new strategies in cell therapy of diabetes mellitus.
Diabetologia 2001;44:407-415
9 洪天配. 干细胞在糖尿病治疗中的应用前景. 国外医学内分泌学分册 2004;24:278-279
10 Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells.
, http://www.100md.com
World J Gastroenterol 2004;10:3016-3020
11 Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O'Neil JJ. In vitro cultivation of human
islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000;97:7999-8004
12 Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic b-cells are formed by self-duplication rather than
stem-cell differentiation. Nature 2004;429:41-46
, 百拇医药
13 Choi Y, Ta M, Atouf F, Lumelsky N. Adult pancreas generates multipotent stem cells and pancreatic and
nonpancreatic progeny. Stem Cells 2004;22:1070-1084
14 Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB, Korbutt G, van der Kooy D. Clonal
identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages.
, http://www.100md.com
Nat Biotechnol 2004;22:1115-1124
15 Suzuki A, Nakauchi H, Taniguchi H. Prospective isolation of multipotent pancreatic progenitors using flow-cytometric
cell sorting. Diabetes 2004;53:2143-2152
16 Weir GC, Bonner-Weir S. b-cell precursors-a work in progress. Nat Biotechnol 2004;22:1095-1096
17 张玲,洪天配, 胡江, 吴永华,李凌松. 胎儿胰腺组织中巢蛋白阳性细胞的分离和体外增生以及诱导分化.
, http://www.100md.com
中国糖尿病杂志 2003;11:416-420
18 张玲,洪天配, 胡江, 刘羿男,吴永华, 李凌松.从胎儿胰腺组织建立单克隆胰腺前体细胞的研究.
中华糖尿病杂志 2004;12:442-445
19 Zhang L, Hong TP, Hu J, Liu YN, Wu YH, Li LS. Nestin-positive progenitor cells isolated from human fetal pancreas
have phenotypic markers identical to mesenchymal stem cells. World J Gastroenterol(in press)
20 Huang H, Tang X. Phenotypic determination and characterization of nestin-positive precursors derived from human
, 百拇医药
fetal pancreas. Lab Invest 2003;83:539-547
21 Wu F, Jagir M, Powell JS. Long-term correction of hyperglycemia in diabetic mice after implantation of cultured
human cells derived from fetal pancreas. Pancreas 2004;29:e23-e29
22 Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express a new class of intermediate filament protein.
Cell 1990;60:585595
, http://www.100md.com
23 Hunziker E, Stein M. Nestin-expressing cells in the pancreatic islets of Langerhans. Biochem Biophys Res Commun
2000;271:116-119
24 夏修金,鲍卫汉, 陈东明, 洪天配,张玲, 郑宗梅,郭文媛. 巢蛋白在人胚胎胰腺中的表达. 中国糖尿病杂志
2003;11:204-207
25 Treutelaar MK, Skidmore JM, Dias-Leme CL, Hara M, Zhang L, Simeone D, Martin DM, Burant CF. Nestin-lineage
cells contribute to the microvasculature but not endocrine cells of the islet. Diabetes 2003;52:2503-2512
, http://www.100md.com
26 Delacour A, Nepote V, Trumpp A, Herrera PL. Nestin expression in pancreatic exocrine cell lineages.
Mech Dev 2004;121:314
27 Gao R, Ustinov J, Pulkkinen MA, Lundin K, Korsgren O, Otonkoski T. Characterization of endocrine progenitor cells
and critical factors for their differentiation in human adult pancreatic cell culture. Diabetes 2003;52:2007-2015
, 百拇医药 28 Humphrey RK, Bucay N, Beattie GM, Lopez A, Messam CA, Cirulli V, Hayek A. Characterization and isolation of
promoter-defined nestin-positive cells from the human fetal pancreas. Diabetes 2003;52:2519-2525
29 Street CN, Lakey JR, Seeberger K, Helms L, Rajotte RV, Shapiro AM, Korbutt GS. Heterogenous expression of nestin
in human pancreatic tissue precludes its use as an islet precursor marker. J Endocrinol 2004;180:213-225
, 百拇医药
30 Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to
insulin-secreting structures similar to pancreatic islets. Science 2001;292:1389-1394
31 Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK. Growth inhibitors promote differentiation of
insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA 2002;99:16105-16110
, http://www.100md.com
32 Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM. Expression of Pax4 in embryonic stem cells
promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA
2003;100: 998-1003
33 Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M. Insulin production by human embryonic
stem cells. Diabetes 2001;50:1691-1697
编辑 张海宁, 百拇医药
洪天配, 男, 1963-07-28生, 博士, 教授, 主任医师, 博士生导师, 福建省南安市人, 汉族.1985年毕业于福建医科大学医学系, 获医学学士学位, 1991年毕业于北京医科大学, 获医学博士学位, 1997-09-06至1999-10-07在丹麦Steno糖尿病中心从事客座研究.主要从事胰岛损伤与功能重建的研究, 参与编写专著和教材4部, 发表论文及综述50篇.现任中华医学会糖尿病分会青年委员、北京糖尿病防治协会理事、北京医学会糖尿病专业委员会委员、中华糖尿病杂志编委、世界华人消化杂志编委等.
国家自然科学基金项目, No. 30040022, No. 30170443
, http://www.100md.com
“211工程”建设项目人体干细胞工程学学科群项目
美国纽约中华医学基金专项人才基金项目
国家973项目子课题, No. 2001CB510105
项目负责人: 洪天配, 100083, 北京市花园北路49号, 北京大学第三医院内分泌科. tpho66@bjmu.edu.cn
电话: 010-62017691 传真: 010-62017700
收稿日期: 2005-01-10 接受日期: 2005-01-19
摘要干细胞根据其来源的不同，可分为胚胎干(ES)细胞和成体干细胞.临床胰岛移植的成功引发了胰岛组织来源不足的巨大压力，从而促使胰腺干细胞研究成为当前的热门课题.理论上，胰腺干细胞可能存在于胰腺组织(如导管上皮)中或由ES细胞分化而来，胰岛细胞还可能来源于其他组织干细胞的横向分化.有关成年胰腺组织中是否存在胰腺干细胞、巢蛋白是否为胰腺干细胞的特异性标志物、巢蛋白阳性细胞在体外是否能真正诱导分化为胰岛素分泌细胞等焦点问题，目前存在激烈的争论.晚近，已从胰腺组织中成功建立了单克隆的多能胰腺干细胞，并在单细胞水平上对胰腺干细胞的体外分化规律进行了初步的描述.同时，多数学者认为巢蛋白不是胰腺干细胞高度特异性的一种标志物，单独应用巢蛋白不足以作为胰腺干细胞的鉴定标准.此外，在有外源性胰岛素存在的培养条件下，单独检测胰岛素的含量和释放反应对于干细胞分化而来的胰岛素产生细胞的鉴定不够可靠，可能出现假阳性结果，建议联合采用多种不同的检测方法.尽管胰腺干细胞研究取得的成果仅仅是初步的，但随着干细胞研究的深入发展和技术突破，必将为糖尿病治疗学领域开辟一片崭新的天地.
, http://www.100md.com
关键词:胰腺干细胞; 糖尿病; 胰岛素
洪天配. 胰腺干细胞研究的现状与展望. 世界华人消化杂志 2005;13(3):286-289
Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the
development and progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med 1993;329:977-986
2 UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared
, http://www.100md.com
with conventional treatment and risk of complications in patients with type 2 diabetes(UKPDS 33). Lancet
1998;352:837-853
3 Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in
seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.
N Engl J Med 2000;343:230-238
, 百拇医药
4 Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of insulin-dependent diabetes using
islets generated in vitro from pancreatic stem cells. Nat Med 2000;6:278-282
5 Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK, Habener JF. Multipotential
nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine,and hepatic phenotypes. Diabetes 2001;50:521-533
, 百拇医药
6 Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell
lines derived from human blastocytes. Science 1998;282:1145-1147
7 Hwang WS, Ryu YJ, Park JH, Park ES, Lee EG, Koo JM, Jeon HY, Lee BC, Kang SK, Kim SJ, Ahn C, Hwang JH,Park KY, Cibelli JB, Moon SY. Evidence of a pluripotent human embryonic stem cell line derived from a cloned
, 百拇医药 blastocyst. Science 2004;303:1669-1674
8 Soria B, Skoudy A, Martin F. From stem cell to beta cells: new strategies in cell therapy of diabetes mellitus.
Diabetologia 2001;44:407-415
9 洪天配. 干细胞在糖尿病治疗中的应用前景. 国外医学内分泌学分册 2004;24:278-279
10 Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells.
, http://www.100md.com
World J Gastroenterol 2004;10:3016-3020
11 Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O'Neil JJ. In vitro cultivation of human
islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000;97:7999-8004
12 Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic b-cells are formed by self-duplication rather than
stem-cell differentiation. Nature 2004;429:41-46
, 百拇医药
13 Choi Y, Ta M, Atouf F, Lumelsky N. Adult pancreas generates multipotent stem cells and pancreatic and
nonpancreatic progeny. Stem Cells 2004;22:1070-1084
14 Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB, Korbutt G, van der Kooy D. Clonal
identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages.
, http://www.100md.com
Nat Biotechnol 2004;22:1115-1124
15 Suzuki A, Nakauchi H, Taniguchi H. Prospective isolation of multipotent pancreatic progenitors using flow-cytometric
cell sorting. Diabetes 2004;53:2143-2152
16 Weir GC, Bonner-Weir S. b-cell precursors-a work in progress. Nat Biotechnol 2004;22:1095-1096
17 张玲,洪天配, 胡江, 吴永华,李凌松. 胎儿胰腺组织中巢蛋白阳性细胞的分离和体外增生以及诱导分化.
, http://www.100md.com
中国糖尿病杂志 2003;11:416-420
18 张玲,洪天配, 胡江, 刘羿男,吴永华, 李凌松.从胎儿胰腺组织建立单克隆胰腺前体细胞的研究.
中华糖尿病杂志 2004;12:442-445
19 Zhang L, Hong TP, Hu J, Liu YN, Wu YH, Li LS. Nestin-positive progenitor cells isolated from human fetal pancreas
have phenotypic markers identical to mesenchymal stem cells. World J Gastroenterol(in press)
20 Huang H, Tang X. Phenotypic determination and characterization of nestin-positive precursors derived from human
, 百拇医药
fetal pancreas. Lab Invest 2003;83:539-547
21 Wu F, Jagir M, Powell JS. Long-term correction of hyperglycemia in diabetic mice after implantation of cultured
human cells derived from fetal pancreas. Pancreas 2004;29:e23-e29
22 Lendahl U, Zimmerman LB, McKay RD. CNS stem cells express a new class of intermediate filament protein.
Cell 1990;60:585595
, http://www.100md.com
23 Hunziker E, Stein M. Nestin-expressing cells in the pancreatic islets of Langerhans. Biochem Biophys Res Commun
2000;271:116-119
24 夏修金,鲍卫汉, 陈东明, 洪天配,张玲, 郑宗梅,郭文媛. 巢蛋白在人胚胎胰腺中的表达. 中国糖尿病杂志
2003;11:204-207
25 Treutelaar MK, Skidmore JM, Dias-Leme CL, Hara M, Zhang L, Simeone D, Martin DM, Burant CF. Nestin-lineage
cells contribute to the microvasculature but not endocrine cells of the islet. Diabetes 2003;52:2503-2512
, http://www.100md.com
26 Delacour A, Nepote V, Trumpp A, Herrera PL. Nestin expression in pancreatic exocrine cell lineages.
Mech Dev 2004;121:314
27 Gao R, Ustinov J, Pulkkinen MA, Lundin K, Korsgren O, Otonkoski T. Characterization of endocrine progenitor cells
and critical factors for their differentiation in human adult pancreatic cell culture. Diabetes 2003;52:2007-2015
, 百拇医药 28 Humphrey RK, Bucay N, Beattie GM, Lopez A, Messam CA, Cirulli V, Hayek A. Characterization and isolation of
promoter-defined nestin-positive cells from the human fetal pancreas. Diabetes 2003;52:2519-2525
29 Street CN, Lakey JR, Seeberger K, Helms L, Rajotte RV, Shapiro AM, Korbutt GS. Heterogenous expression of nestin
in human pancreatic tissue precludes its use as an islet precursor marker. J Endocrinol 2004;180:213-225
, 百拇医药
30 Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to
insulin-secreting structures similar to pancreatic islets. Science 2001;292:1389-1394
31 Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK. Growth inhibitors promote differentiation of
insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA 2002;99:16105-16110
, http://www.100md.com
32 Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM. Expression of Pax4 in embryonic stem cells
promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA
2003;100: 998-1003
33 Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M. Insulin production by human embryonic
stem cells. Diabetes 2001;50:1691-1697
编辑 张海宁, 百拇医药
