RESEARCH ARTICLE

Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study

  • Ranhua JIANG 1 ,
  • Zhibo HAN 2 ,
  • Guangsheng ZHUO 3 ,
  • Xiaodan QU 1 ,
  • Xue LI 1 ,
  • Xin WANG 3 ,
  • Yuankang SHAO 3 ,
  • Shimin YANG 1 ,
  • Zhong Chao HAN , 2
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  • 1. Liaoyang Diabetic Hospital, Liaoyang 111000, China
  • 2. National Engineering Research Center of Stem Cells, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin 300020, China
  • 3. Beijing Health-Biotech. Co., Ltd., Beijing 100176, China

Received date: 27 Dec 2010

Accepted date: 13 Jan 2011

Published date: 05 Mar 2011

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Mesenchymal stem cells (MSC) have been used in clinical trials for severe diabetes, a chronic disease with high morbidity and mortality. Bone marrow is the traditional source of human MSC, but human term placenta appears to be an alternative and more readily available source. Here, the therapeutic effect of human placenta-derived MSC (PD-MSC) was studied in type 2 diabetes patients with longer duration, islet cell dysfunction, high insulin doses as well as poor glycemic control in order to evaluate the safety, efficacy and feasibility of PD-MSC treatment in type 2 diabetes (T2D). Ten patients with T2D received three intravenous infusions of PDSC, with one month interval of infusion. The total number of PDSC for each patient was (1.22–1.51) × 106/kg, with an average of 1.35 × 106/kg. All of the patients were followed up after therapy for at least 3 months. A daily mean dose of insulin used in 10 patients was decreased from 63.7€±€18.7 to 34.7€±€13.4 IU (P<0.01), and the C-peptide level was increased from 4.1€±€3.7 ng/mL to 5.6€±€3.8 ng/mL (P<0.05) respectively after therapy. In 4 of 10 responders their insulin doses reduced more than 50% after infusion. The mean levels of insulin and C-peptide at each time point in a total of 10 patients was higher after treatment (P<0.05). No fever, chills, liver damage and other side effects were reported. The renal function and cardiac function were improved after infusion. The results obtained from this pilot clinical trial indicate that transplantation of PD-MSC represents a simple, safe and effective therapeutic approach for T2D patients with islet cell dysfunction. Further large-scale, randomized and well-controlled clinical studies will be required to substantiate these observations.

Cite this article

Ranhua JIANG , Zhibo HAN , Guangsheng ZHUO , Xiaodan QU , Xue LI , Xin WANG , Yuankang SHAO , Shimin YANG , Zhong Chao HAN . Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study[J]. Frontiers of Medicine, 2011 , 5(1) : 94 -100 . DOI: 10.1007/s11684-011-0116-z

1
Yang W, Lu J, Weng J P, Jia W, Ji L, Xiao J, Shan Z, Liu J, Tian H, Ji Q, Zhu D, Ge J, Lin L, Chen L, Guo X, Zhao Z, Li Q, Zhou Z, Shan G, He J. Prevalence of diabetes among men and women in China. N Engl J Med, 2010, 362(12): 1090–1101

DOI PMID

2
Hu D, Sun L, Fu P, Xie J, Lu J, Zhou J, Yu D, Whelton P K, He J, Gu D. Prevalence and risk factors for type 2 diabetes mellitus in the Chinese adult population: the InterASIA Study. Diabetes Res Clin Pract, 2009, 84(3): 288–295

DOI PMID

3
Kobayashi N, Yuasa T, Okitsu T. Regenerative medicine for diabetes mellitus. Cell Transplant, 2009, 18(5): 491–496

PMID

4
Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, Li H, Li H, Jiang Y, An Y, Shuai Y, Zhang B, Zhang J, Thompson TJ, Gerzoff RB, Roglic G, Hu Y, Bennett PH. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet, 2008; 24:371(9626):1783–1789

5
Ciceri F, Piemonti L.Bone marrow and pancreatic islet: an old story with new perspectives. Cell Transplant, 2010<month>Aug</month><day>17</day>

6
Kodama S, Kühtreiber W, Fujimura S, Dale E A, Faustman D L. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science, 2003, 302(5648): 1223–1227

DOI PMID

7
Pittenger M F, Mackay A M, Beck S C, Jaiswal R K, Douglas R, Mosca J D, Moorman M A, Simonetti D W, Craig S, Marshak D R. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411): 143–147

DOI PMID

8
Deans R J, Moseley A B. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol, 2000, 28(8): 875–884

DOI PMID

9
Gronthos S, Franklin D M, Leddy H A, Robey P G, Storms R W, Gimble J M. Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol, 2001, 189(1): 54–63

DOI PMID

10
Erices A, Conget P, Minguell J J. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol, 2000, 109(1): 235–242

DOI PMID

11
Lu L L, Liu Y J, Yang S G, Zhao Q J, Wang X, Gong W, Han Z B, Xu Z S, Lu Y X, Liu D, Chen Z Z, Han Z C. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica, 2006, 91(8): 1017–1026

PMID

12
In ’t Anker P S, Scherjon S A, Kleijburg-van der Keur C, de Groot-Swings G M, Claas F H, Fibbe W E, Kanhai H H. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells, 2004, 22(7): 1338–1345

DOI PMID

13
Zheng C L, Yang S G, Guo Z X, Liao W, Zhang L, Yang R, Han Z C. Human multipotent mesenchymal stromal cells from fetal lung expressing pluripotent markers and differentiating into cell types of three germ layers. Cell Transplant, 2009, 18(10): 1093–1109

DOI PMID

14
Chen K, Wang D, Du W T, Han Z B, Ren H, Chi Y, Yang S G, Zhu D, Bayard F, Han ZC. Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism. Clin Immunol, 2010, 135(3): 448–458

DOI PMID

15
Wang D, Chen K, Du W T, Han Z B, Ren H, Chi Y, Yang S G, Bayard F, Zhu D, Han Z C. CD14+ monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells. Exp Cell Res, 2010, 316(15): 2414–2423

DOI PMID

16
Liao W B, Xie J, Zhong J, Liu Y J, Du L, Zhou B, Xu J, Liu P X, Yang S G, Wang J M, Han Z B, Han Z C. Therapeutic effect of human umbilical cord multipotent mesenchymal stromal cells in a rat model of stroke. Transplantation, 2009, 87(3): 350–359

DOI PMID

17
Zhao Q J, Ren H Y, Li X Y, Chen Z, Zhang X Y, Gong W, Liu Y J, Pang T X, Han Z C. Differentiation of Human umbilical cord mesenchymal stem cells into low immunogenic hepatocyte-like cells. Cytotherapy, 2009, 11(4): 414–426

18
Wu K H, Mo X M, Zhou B, Lu S H, Yang S G, Liu Y L, Han Z C. Cardiac potential of stem cells from whole human umbilical cord tissue. J Cell Biochem, 2009, 107(5): 926–932

DOI PMID

19
Garcia-Olmo D, Herreros D, Pascual I, Pascual J A, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum, 2009, 52(1): 79–86

PMID

20
Hare J M, Traverse J H, Henry T D, Dib N, Strumpf R K, Schulman S P, Gerstenblith G, DeMaria A N, Denktas A E, Gammon R S, Hermiller J B Jr, Reisman M A, Schaer G L, Sherman W. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol, 2009, 54(24): 2277–2286

DOI PMID

21
Horwitz E M, Prockop D J, Fitzpatrick L A, Koo W W, Gordon P L, Neel M, Sussman M, Orchard P, Marx J C, Pyeritz R E, Brenner M K. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med, 1999, 5(3): 309–313

DOI PMID

22
Kebriaei P, Isola L, Bahceci E, Holland K, Rowley S, McGuirk J, Devetten M, Jansen J, Herzig R, Schuster M, Monroy R, Uberti J. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant, 2009, 15(7): 804–811

DOI PMID

23
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo M E, Remberger M, Dini G, Egeler R M, Bacigalupo A, Fibbe W, Ringdén O. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet, 2008, 371(9624): 1579–1586

DOI PMID

24
Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, Ringdén O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet, 2004, 363(9419): 1439–1441

DOI PMID

25
Lee P H, Kim J W, Bang O Y, Ahn Y H, Joo I S, Huh K. Autologous mesenchymal stem cell therapy delays the progression of neurological deficits in patients with multiple system atrophy. Clin Pharmacol Ther, 2008, 83(5): 723–730

DOI PMID

26
Bhansali A, Upreti V, Khandelwal N, Marwaha N, Gupta V, Sachdeva N, Sharma R R, Saluja K, Dutta P, Walia R, Minz R, Bhadada S, Das S, Ramakrishnan S. Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev, 2009, 18(10): 1407–1416

DOI PMID

27
Lin G, Wang G, Liu G, Yang L J, Chang L J, Lue T F, Lin C S. Treatment of type 1 diabetes with adipose tissue-derived stem cells expressing pancreatic duodenal homeobox 1. Stem Cells Dev, 2009, 18(10): 1399–1406

DOI PMID

28
Liu M, Han Z C. Mesenchymal stem cells: biology and clinical potential in type 1 diabetes therapy. J Cell Mol Med, 2008, 12(4): 1155–1168

DOI PMID

29
Santana A, Enseñat-Waser R, Arribas M I, Reig J A, Roche E. Insulin-producing cells derived from stem cells: recent progress and future directions. J Cell Mol Med, 2006, 10(4): 866–883

DOI PMID

30
Wang H S, Shyu J F, Shen W S, Hsu H C, Chi T C, Chen C P, Huang S W, Shyr Y M, Tang K T, Chen T H. Transplantation of insulin producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. Cell Transplant, 2010<month>Aug</month><day>18</day>

31
Zhang Y, Dou Z. Transdifferentiation of bone marrow mesenchymal stem cell into islet cells to treat diabetes mellitus. J Cell Biol, 2007, 29: 1–5

32
Brooke G, Rossetti T, Pelekanos R, Ilic N, Murray P, Hancock S, Antonenas V, Huang G, Gottlieb D, Bradstock K, Atkinson K. Manufacturing of human placenta-derived mesenchymal stem cells for clinical trials. Br J Haematol, 2009, 144(4): 571–579

DOI PMID

33
Tran T C, Kimura K, Nagano M, Yamashita T, Ohneda K, Sugimori H, Sato F, Sakakibara Y, Hamada H, Yoshikawa H, Hoang S N, Ohneda O. Identification of human placenta-derived mesenchymal stem cells involved in re-endothelialization. J Cell Physiol, 2011, 226(1): 224–235

DOI PMID

34
Fukuchi Y, Nakajima H, Sugiyama D, Hirose I, Kitamura T, Tsuji K. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells, 2004, 22(5): 649–658

DOI PMID

35
Hwang J H, Shim S S, Seok O S, Lee H Y, Woo S K, Kim B H, Song H R, Lee J K, Park Y K. Comparison of cytokine expression in mesenchymal stem cells from human placenta, cord blood, and bone marrow. J Korean Med Sci, 2009, 24(4): 547–554

DOI PMID

36
Parolini O, Alviano F, Bagnara G P, Bilic G, Bühring H J, Evangelista M, Hennerbichler S, Liu B, Magatti M, Mao N, Miki T, Marongiu F, Nakajima H, Nikaido T, Portmann-Lanz C B, Sankar V, Soncini M, Stadler G, Surbek D, Takahashi T A, Redl H, Sakuragawa N, Wolbank S, Zeisberger S, Zisch A, Strom S C. Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells, 2008, 26(2): 300–311

DOI PMID

37
Dzierzak E, Robin C. Placenta as a source of hematopoietic stem cells. Trends Mol Med, 2010, 16(8): 361–367

DOI PMID

38
Lee L K, Ueno M, Van Handel B, Mikkola H K. Placenta as a newly identified source of hematopoietic stem cells. Curr Opin Hematol, 2010, 17(4): 313–318

DOI PMID

39
Evangelista M, Soncini M, Parolini O. Placenta-derived stem cells: new hope for cell therapy? Cytotechnology, 2008, 58(1): 33–42

DOI PMID

40
Zhou J, Ma X J, Bao Y Q, Pan X P, Lu W, Hu C, Xiang K S, Jia W P. Study on prevalence of latent autoimmune diabetes in adults and its relationship with metabolic syndrome. Zhonghua Yi Xue Za Zhi, 2009, 89(18): 1250–1254

PMID

41
Salem H K, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells, 2010, 28(3):585–596

42
Phinny D G, Prockop D J. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells, 2007, 25(11):2896–2902.

43
Horwitz E M, Prather W R. Cytokines as the major mechanism of mesenchymal stem cell clinical activity: expanding the spectrum of cell therapy. Isr Med Assoc J, 2009, 11(4): 209–211

PMID

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