This poster presents the process for treating severe autoimmune diabetes in mice through the use of bone marrow-derived endothelial cells

Rowland, Linda M.

VanMorlan, Amie

Wan, Xiaoxiao, 1980-

Zaghouani, Habib

English

University of Missouri: MOspace

Reversal of Severe Autoimmune Diabetes at The Stem Cell Level By Bone Marrow-derived Endothelial Progenitors  Xiao Wan*, Linda M. Rowland, Amie VanMorlan and Habib Zaghouani.   University of Missouri School of Medicine, Columbia, MO, USA, 65212 Introduction Type 1 diabetes (T1D): 1.  Autoimmune: Infiltration of lymphocytes into pancreatic islets  Results  1. Both tolerogen and donor bone marrow are required for reversal of T1D 2. Increased β cell proliferation in treated mice Conclusions -This project was funded by NIH grants. However, only control of islet infiltration is not sufficient to reverse overt T1D  Combination strategy Normal Diabetic 2.  Critical loss of insulin-producing β cells Normal Diabetic 3.  High blood glucose level with clinical complications: • Heart disease • High blood pressure • Blindness • Kidney failure • Nerve damage • Amputation • Poor vascularization 4.  Classic  strategy for therapy of type 1 diabetes: • Effective control of inflammation to facilitate β cell regeneration/ replication/ differentiation  Diabetic Tolerogen Even after tolerogen treatment that effectively inhibited islet infiltration, there is no sign of restoration of β cell mass, and these mice still maintain high blood glucose levels. What is the problem? Strikingly impaired micro-vascularization in pancreatic islets in T1D Normal BGL: 89  Diabetic (BGL: 303) Diabetic BGL: 438 Intra-islet vascularization is essential for in vivo maintenance of β cells and transportation of insulin PECAM1 Insulin Restore functional islet vascularization in  diabetic mice by bone marrow transfer Bone marrow GFP mouse Diabetic mouse Diabetic mouse control tolerogen Blood Glucose levels Days post diabetes β cell regeneration in treated mice? Tolerogen (n=8) BM+Tolerogen (n=14) BM+control (n=14) BM+Tolerogen BM+control A. Increased β cell mass in treated mice B. Proliferation of β cells in treated mice Insulin/ki-67/DAPI Insulin/ki-67/DAPI Insulin/ki-67 Insulin/ki-67 Normal BM+Tolerogen Mechanisms underlying β cell regeneration? 3. Donor Bone marrow derived cells do not differentiate into mature β cells Insulin GFP BM+Tolerogen 4. Restored intra-islet vascularization in treated mice BM+Tolerogen BM+control Tolerogen Donor bone marrow-derived endothelial cells? 5. Donor bone marrow-derived endothelial cells in treated mice BM+Tolerogen PECAM1 / GFP GFP / Insulin PECAM1/ GFP / Insulin 6. Decreased endothelial progenitor cells in the bone marrow of diabetic mice How about transfer of purified endothelial progenitors from the bone marrow? 7. Transfer of purified endothelial progenitor cells instead of whole bone marrow  restored T1D 1. Restoration of functional islet vascularization is critical for β cell regeneration 2. Control of inflammation is the basis of the protection 3. Angiogenic therapies should be combined with immunomodulatory therapies to revserse T1D. It is time to think about autoimmune diabetes at the stem cell level! PECAM1 Insulin R3R30.02 FLK-1 c-Kit Healthy Diabetic 0.03 R3R3Isotype 0.5 1.6 Lin−c-Kit+FLK-1+ cells (%) Healthy Diabetic ** 3 2 1 0 Percent of diabetes free 0 20 40 60 80 100 0 20 40 100 60 80 Tolerogen+FLK-1−  (n=5) Tolerogen (n=3) Tolerogen+FLK-1+  (n=6) FLK-1+  (n=3) Days post diabetes 

Reversal of severe autoimmune diabetes at the stem cell level by bone marrow-derived endothelial progenitors

https://mospace.umsystem.edu/xmlui/bitstream/10355/16024/1/ReversalSevereAutoimmuneDiabetes.pdf

Reversal of severe autoimmune diabetes at the stem cell level by bone marrow-derived endothelial progenitors

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