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

Abstract

IntroductionMesenchymal 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).MethodsExperimental 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 1x106 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 β cell mass, regulatory T cell population, cytokine profile and cell biodistribution were evaluated after ADMSCs/PBS administration.ResultsADMSCs 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 β 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-β 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.ConclusionConsidering 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0017-1) contains supplementary material, which is available to authorized users.

In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model

“…All these shortcomings prompted development of new methods to monitor MSC PK/PD. Recently, the development of in vivo noninvasive imaging methodologies has provided one kind of tool to examine delivery, grafting, distribution, and survival of MSCs after IA injection [6, 8, 9]. However, detection sensitivity or threshold of MSC numbers that could be detected in vivo has not been fully investigated in these noninvasive imaging methodologies.…”

Efficacy and Safety of Allogenic Canine Adipose Tissue-derived Mesenchymal Stem Cell Therapy for Insulin Dependent Diabetes Mellitus in Dogs: A pilot study

“…Therefore, the therapeutic effects of stem cells [22][23][24][25][26] may involve both transplantation of new beta cells and preservation of the remaining beta cells. It has been reported that insulin secretory capacity was improved in human diabetic patients as well as in laboratory diabetic model animals [27,30] when AT-MSCs were administered via a venous or splenic route. However, to date, no studies had been performed in dogs suffering from IDDM for more than 1 year.…”

Direct comparison of the abilities of bone marrow mesenchymal versus hematopoietic stem cells to reverse hyperglycemia in diabetic NOD.SCID mice

“…A subsequent study further identified the active cell fraction as bearing hematopoietic lineage markers such as CD34 and CD133 but not CD38. 41 A different approach was adopted by Luo et al 42 who separated mouse BMSC using a variety of HSC cell surface markers. A Sca + /Mac-1 − cell fraction was shown to be most effective in infiltrating islets in vivo.…”