Immunomodulatory Function of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Type 1 Diabetes

Abstract

Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.

Comparative study of immune regulatory properties of stem cells derived from different tissues

“…However, the immune modulatory function of BM-MSCs has been documented in graftversus-host disease [4][5][6], autoimmune encephalomyelitis [17], sepsis [3], collagen-induced arthritis, and bowel inflammation [15,16,20]. But whether other SC categories have the ability to exert comparable effects was unknown and our results provide novel information supporting the view that a variety of SCs share the critical aspect of being immune privileged.…”

“…Several SC subtypes, including neural SCs [10] and mesenchymal stromal cells (MSCs) [11][12][13][14], possess regenerative potential and may interact with immune effector cells (IECs), profoundly influencing their function in vitro and in vivo. The immune system plays a critical role in the pathogenesis and progression of a number of degenerative diseases, raising the possibility that SCs may be effective in repairing the damaged organ by promoting cell formation and modulating the associated immune response [6,[14][15][16][17][18][19][20]. Based on this premise, the immunogenicity and immune modulatory properties of SCs have to be carefully characterized to decipher their potential clinical import.…”

“…However, they indirectly activate resident SCs, enhancing the repair of the organ [70][71][72]. Because of these characteristics, therapeutically, MSCs and MSC-like SCs may have to be repeatedly employed to exert their role long-term, in absence of clear evidence of their homing and persistence inside the tissues [14][15][16][17][18][19][20]. Conversely, the delivery of tissue-specific multipotent adult SCs, such as CSCs and LSCs, to the corresponding damaged organ fails to stimulate the resident SCs nested in proximity to or distant from the injured parenchyma [73,74].…”

Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoimmune arthritis

“…[5][6][7] To date, bone marrow-derived MSCs (BM-MSCs) are among the most commonly used MSCs in pre-clinical research for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases. [8][9][10] However, there are some limitations associated with BM-MSCs in clinical applications, including the technical difficulty in acquiring sufficient numbers of cells for therapy. 11 Recently, olfactory ecto-mesenchymal stem cells (OE-MSCs), a new type of resident stem cell in the olfactory lamina propria, have been characterized.…”

Applicability of Adipose-Derived Stem Cells in Type 1 Diabetes Mellitus

“…The results showed that ADSCs would have better clinical applicability, since the neoplasm may occur when using autologous MSCs in NOD mice (33,106). Alternatively, recent reports have highlighted the therapeutic potential of ADSCs for congenital causes or acquired factors of diabetes.…”