Mia Aguilar

Introduction. The chronic-autoimmune disease type 1 diabetes mellitus (T1D) affects millions of people worldwide with incident rates continuing to rise 3-4% every year over the past 30 years.¹ Antigen Presenting Cells (APCs) presenting β cell peptides to autoreactive CD4+ T lymphocytes in the pancreatic lymph nodes. Attachment of the T-cell receptor to the MHC complex, causes the activation of autoreactive CD8+ T cells which lyse the β cells expressing the self-antigen on MHC I. 1 Repeated manual testing of blood sugar levels with subcutaneous exogenous insulin injections is the primary method of treatment.²  Although it improves effects of T1D, it does not decrease its progression or aid in prevention. The immunomodulatory potency of mesenchymal stem cells (MSCs), non-hematopoietic multipotent cells acting through direct contact with immune cells and/or affecting local microenvironmental factors, are being investigated to prolong the utility of these cells.³ Properties of MSCs that affect T-cells such as its Wild-type p53-induce phosphatase 1 (Wip1) gene, overexpression of Alpha-1 Antitrypsin (AAT), and antigen specific immunity will be investigated to identify their potential in treating T1D. ^3,4,5  Methods.  Wip1^+/+MSCs and Wip1^−/−MSCs were intravenously administered to STZ-induced T1DM mice. Flow cytometry was used to detect IFN-γ in CD4+Th1 cells of spleen lymphocytes in each group. Proinflammatory factors in T1D, IL-17a and IL-4, were assessed too. ³ To identify effects of overexpression of ATT, there was an overexpression of hAAT in MSCs in NOD mice. Factors VCAM1, MMP-2, Sox9, and IGF-1 in supernat were assessed.⁴  To identify antigen specificity in MSCs, theu were incubated with fluorescent quenched Ovalbumin protein and assessed through florescence microscopy.⁵  Results.  Percentage of Th1 cells in the Wip1−/−MSCs group was between that of the T1DM group and the Wip1+/+MSCs group. In comparison, serum IFN-γ and IL-17a increased and IL-4 decreased in the Wip1−/−MSCs infusion group.³ Overexpression of AAT showed factors such as VCAM1, MMP-2, Sox9, and IGF-1 that supported the improved intrinsic properties of hAAT-MSCs through enhanced stemness and differentiation.⁴ MSCs were able to take up and process OVA-DQ, as demonstrated by fluorescence.⁵  Conclusion.  Data indicated that Wip1 is critical for the immunomodulatory activity of MSCs in T1DM mice.³ Factors expressed by MSCs with overexpression of AAT supported the improved intrinsic properties through enhanced stemness and differentiation of hAAT‐MSCs.⁴ Activated MSCs could be beneficial in targeting antigens or peptides with MSCs for therapeutic purposes.⁵ MSCs have therapeutic potency that could aid in the progression and prevention of T1D.

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2. Akil AA, Yassin E, Al-Maraghi A, Aliyev E, Al-Malki K, Fakhro KA. Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era. J Transl Med. 2021;19(1):137. Published 2021 Apr 1. doi:10.1186/s12967-021-02778-6
3. Zhou N, Liu W, Zhang W, et al. Wip1 regulates the immunomodulatory effects of murine mesenchymal stem cells in type 1 diabetes mellitus via targeting IFN-α/BST2. Cell Death Discov. 2021;7(1):326. Published 2021 Oct 29. doi:10.1038/s41420-021-00728-1
4. Song, L., Gou, W., Wang, J., Wei, H., Lee, J., Strange, C., & Wang, H. (2021). Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice. Stem cells translational medicine, 10(2), 320–331. https://doi.org/10.1002/sctm.20-0122
5. van Megen KM, van ‘t Wout ET, Lages Motta J, Dekker B, Nikolic T, Roep BO. Activated Mesenchymal Stromal Cells Process and Present Antigens Regulating Adaptive Immunity. Front Immunol. 2019;10:694. Published 2019 Apr 3. doi:10.3389/fimmu.2019.00694