Diabetes Res Clin Pract. 2016 Nov;121:102-111. doi: 10.1016/j.diabres.2016.09.008.

Intravenous vs intraperitoneal transplantation of umbilical cord mesenchymal stem cells from Wharton’s jelly in the treatment of streptozotocin-induced diabetic rats.

El-Hossary N1, Hassanein H2, El-Ghareeb AW3, Issa H4.
1 Department of Biotechnology, Faculty of Science, Cairo University, Cairo, Egypt. Electronic address: nancyelhossary@gmail.com.
2 Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt.
3 Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt.
4 Department of Clinical Pathology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt; Cell Safe Cord Blood Bank, Dar El Mona Health Care Resort, Giza, Egypt.

 

Abstract

AIM:

To evaluate the efficiency of mesenchymal stem cells isolated from Wharton’s jelly (WJ-MSCs) through either the intravenous or intraperitoneal transplantations into streptozotocin (STZ)-induced diabetic rats as a therapy for type 1 diabetes mellitus (T1DM).

METHODOLOGY:

A rat model with STZ induction was established and the rats were divided into 3 groups: a tail vein injection group, an intraperitoneal injection group and a STZ control group. Following transplantation, blood glucose levels were monitored weekly then the pancreatic tissues were collected to examine the pancreatic islets by histopathology and morphometric studies.

RESULTS:

Intravenous transplantation of WJ-MSCs ameliorated hyperglycemia at day 7 after transplantation, with sustained decreased fasting blood glucose (FBG) levels until day 56. Further, these cells ameliorated at least partially the damage induced by STZ in the pancreas and produced a similar morphology to normal islets. On the contrary, intraperitoneal transplantation of WJ-MSCs failed to maintain normoglycemia or ameliorate the damaged pancreas in STZ-injected rats.

CONCLUSION:

These findings conclude that the intravenous administration method was effective in transplanting WJ-MSCs for the treatment of T1DM, whereas the intraperitoneal transplantation showed no therapeutic effect in our animal experiments. Copyright © 2016 Elsevier Ireland Ltd.

KEYWORDS:

Intraperitoneal; Intravenous; Mesenchymal stem cell; Transplantations; Type 1 diabetes; Wharton’s jelly

PMID: 27693839

 

Supplement:

Regenerative medicine, the process of restoring diseased or damaged tissue by replacing it with biological substitutes represents one of the main concerns of medicine. As shown in (Figure1), WJ-MSCs are easily obtained and processed. Moreover, they exhibit self-renewal, plastic adherence, large differentiation potential in vivo, and possess immune-modulatory properties, which prevent rejections from occurring, even after xenotransplantation of post differentiated MSCs without immunosuppression [1, 2].

 

 

Figure 1. Umbilical cord: cross section: Structure of human umbilical cord which contains two arteries and one vein surrounded by Wharton`s jelly and amniotic epithelium [3]

 

As shown in (Figure 2), different administration methods of stem cells have been investigated in both animal models and humans in many previous studies to treat diabetes mellitus. Although diabetes mellitus is caused by destruction of the beta cells within the pancreatic islets, no studies have attempted transplantation directly into the pancreas. This is because the pancreas is very sensitive organ and is vulnerable to mechanical intervention. MSCs have been tested using different methods. Cells can be grafted underneath the kidney capsule [4], delivered via the portal vein injection [5], grafted into the liver [6, 7], or injected into the tail vein [8] . However, there is a little research comparing the efficiency of these methods. In this context, the purpose of our study was to compare the therapeutic efficacy of transplanting WJ-MSCs via two different methods (tail-vein injection and intraperitoneal injection) in the treatment of streptozotocin (STZ)-induced diabetic rats in vivo.

 

 

Figure 2. Methods of MSCs transplantation. Stem cells or insulin-producing cells (IPCs) can be transplanted via the tail vein, intraperitoneally, under the kidney capsule, into the liver, or via the portal vein [3].

 

The results showed that the intravenous administration of WJ-MSCs exhibited better potential in maintaining control of hyperglycemia in STZ-diabetic rats than the intraperitoneal administration did . These results strongly indicate that intravenous transplantation of  WJ-MSCs can be considered an excellent candidate for DM cell therapy .

Our  results were consistent with the hypothesis suggested that MSCs transplanted through intravenous injection possess tissue repair and cytoprotective properties through migration to acutely- injured tissue, where high-level chemokines, including vascular cell adhesion molecule-1(VCAM-1), stromal derived factor (SDF), monocyte chemotactic factor 1(MCP-1), CX3CL1- CX3CR1, and CXCL12-CXCR4 are expressed [9-11]. Briefly, MSCs showed the ability to express some chemokine receptors like CXC receptor 4 (CXCR4]), CX3C receptor 1 (CX3CR1), CXCR6, CC chemokine receptor 1 (CCR1) and CCR7 [11], which were attempted to combine the chemokines released from pancreatic cells such as CXC ligand I2 (CXCL12), CX3CL1, CXCL16, CC chemokine ligand 3 (CCL3) and CCL19 as a response to MSCs migration into injury of the pancreas.

Although the mechanisms by which MSCs attracted in tissue and migrate across endothelial cell layers are not yet fully understood, it is possible that this process involved chemokines and their receptors, similar to the migration process of leukocytes into sites of inflammation [12]. Overall, our findings in this study conclude that transplantation of WJ-MSCs via the intravenous administration route showed high potential to ameliorate hyperglycemia in vivo in STZ-induced diabetic rats. Moreover, we suggested that due to a deficiency in stem cell homing, the WJ-MSCs transplantation via intraperitoneal administration route had no therapeutic effect on STZ- induced diabetic rats.

 

References:

[1] Troyer DL, Weiss ML. Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells 2008;26:591-9.

[2] Chao KC, Chao KF, Fu YS, Liu SH. Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS ONE 2008;3:e1451.

[3] Iancu C, Ilie I, Mocan L, Georgescu C, Ilie R, Duncea I, et al. Human cord blood-derived stem cells in transplantation and regenerative medicine. Stem Cells in Clinic and Research. 2011.

[4] Rackham CL, Chagastelles PC, Nardi NB, Hauge-Evans AC, Jones PM, King AJ. Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice. Diabetologia. 2011;54:1127-35.

[5] Wu XH, Liu CP, Xu KF, Mao XD, Zhu J, Jiang JJ, et al. Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells. World J Gastroenterol. 2007;13:3342-9.

[6] Wang HS, Shyu JF, Shen WS, Hsu HC, Chi TC, Chen CP, et al. Transplantation of insulin-producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. Cell Transplant. 2011;20:455-66.

[7] Chao KC, Chao KF, Fu YS, Liu SH. Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One. 2008;3:e1451.

[8] Dinarvand P, Hashemi SM, Soleimani M. Effect of transplantation of mesenchymal stem cells induced into early hepatic cells in streptozotocin-induced diabetic mice. Biol Pharm Bull. 2010;33:1212-7.

[9] Lin P, Chen L, Li D, Yang N, Sun Y, Xu Y. Dynamic analysis of bone marrow mesenchymal stem cells migrating to pancreatic islets using coculture microfluidic chips: An accelerated migrating rate and better survival of pancreatic islets were revealed. Neuro Endocrinol Lett. 2009;30:204-8.

[10] Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A. 2006;103:17438-43.

[11] Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, et al. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood. 2005;106:419-27.

[12] Ransohoff RM. Chemokines and Chemokine Receptors: Standing at the Crossroads of Immunobiology and Neurobiology. Immunity.31:711-21.