Therapeutic efficacy and biodistribution of allogeneic mesenchymal stem cells delivered by intrasplenic and intrapancreatic routes in streptozotocin-induced diabetic mice

Author(s)

Ueda Yaochite, Juliana Navarro ^[1] ; Caliari-Oliveira, Carolina ^[1] ; Botelho de Souza, Lucas Eduardo ^[2] ; Neto, Lourenco Sbragia ^[3] ; Bonini Palma, Patricia Vianna ^[4] ; Covas, Dimas Tadeu ^[2] ; Ribeiro Malmegrim, Kelen Cristina ^[5] ; Voltarelli, Julio Cesar ; Donadi, Eduardo Antonio ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Biochem & Immunol, Basic & Appl Immunol Program, Sch Med Ribeirao Preto, BR-14049900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Clin Med, Sch Med Ribeirao Preto, BR-14049900 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Surg & Anat, Sch Med Ribeirao Preto, Div Pediat Surg, BR-14049900 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Reg Blood Ctr Ribeirao Preto, BR-14051140 Sao Paulo - Brazil

^[5] Univ Sao Paulo, Dept Clin Toxicol & Bromatol Anal, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Sao Paulo - Brazil

• Document type: Journal article
• Source: STEM CELL RESEARCH & THERAPY; v. 6, MAR 14 2015.
• Web of Science Citations: 16

Abstract

Introduction: Mesenchymal stromal/stem cells (MSCs) are multipotent cells that have the ability to express and secrete a wide range of immunomodulatory molecules, cytokines, growth factors and antiapoptotic proteins. MSCs modulate both innate and adaptive immune responses making them potential candidates for the treatment of patients with type 1 diabetes mellitus (T1D). However, one problem frequently associated with the systemic MSCs administration is the entrapment of the cells mainly in the lungs. In this sense, trying to avoid the lung barrier, the purpose of this study was to evaluate the long-term therapeutic efficacy and biodistribution of allogeneic adipose tissue-derived MSCs (ADMSCs) injected via two different delivery routes (intrasplenic/I. Sp and intrapancreatic/I. Pc) in a murine model of diabetes induced by streptozotocin (STZ). Methods: Experimental diabetes was induced in C57BL/6 male mice by multiple low-doses of STZ. MSCs were isolated from adipose tissue (ADMSCs) of Balb/c mice. A single dose of 1x10(6) ADMSCs was microinjected into the spleen or into the pancreas of diabetic mice. Control group received injection of PBS by I. Sp or I. Pc delivery routes. Glycemia, peripheral glucose response, insulin-producing beta cell mass, regulatory T cell population, cytokine profile and cell biodistribution were evaluated after ADMSCs/PBS administration. Results: ADMSCs injected by both delivery routes were able to decrease blood glucose levels and improve glucose tolerance in diabetic mice. ADMSCs injected by I. Sp route reverted hyperglycemia in 70% of diabetic treated mice, stimulating insulin production by pancreatic beta cells. Using the I. Pc delivery route, 42% of ADMSCs-treated mice responded to the therapy. Regulatory T cell population remained unchanged after ADMSCs administration but pancreatic TGF-beta levels were increased in ADMSCs/I. Sp-treated mice. ADMSCs administrated by I. Sp route were retained in the spleen and in the liver and ADMSCs injected by I. Pc route remained in the pancreas. However, ADMSCs injected by these delivery routes remained only few days in the recipients. Conclusion: Considering the potential role of MSCs in the treatment of several disorders, this study reports alternative delivery routes that circumvent cell entrapment into the lungs promoting beneficial therapeutic responses in ADMSCs-treated diabetic mice. (AU)

• FAPESP's process: 08/57877-3 - National Institute of Science and Technology in Cell Therapy
• Grantee: Roberto Passetto Falcão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/11759-0 - Comparative analysis of mesenchymal stromal cells derived from patients with type 1 diabetes mellitus and healthy individuals regarding the therapeutic potential in the treatment of experimental diabetes
• Grantee: Juliana Navarro Ueda Yaochite
• Support Opportunities: Scholarships in Brazil - Doctorate