Bone marrow cells produce nerve growth factor and promote angiogenesis around transplanted islets

Abstract

Aim: To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets.

Methods: Streptozotocin induced diabetic BALB/c mice were transplanted syngeneically under the kidney capsule with the following: (1) 200 islets (islet group: n = 12), (2) 1-5 x 10(6) bone marrow cells (bone marrow group: n = 11), (3) 200 islets and 1-5 x 10(6) bone marrow cells (islet + bone marrow group: n = 13), or (4) no cells (sham group: n = 5). All mice were evaluated for blood glucose, serum insulin, serum nerve growth factor (NGF) and glucose tolerance (GTT) up to postoperative day (POD) 14. Histological assessment for insulin, von Willebrand factor (vWF) and NGF was performed at POD 3, 7 and 14.

Results: Blood glucose level was lowest and serum insulin was highest in the islet + bone marrow group. Serum NGF increased in islet, bone marrow, and islet + bone marrow groups after transplantation, and there was a significant difference (P = 0.0496, ANOVA) between the bone marrow and sham groups. The number of vessels within the graft area was significantly increased in both the bone marrow and islet + bone marrow groups at POD 14 as compared to the islet alone group (21.2 +/- 3.6 in bone marrow, P = 0.01, vs islet group, 22.6 +/- 1.9 in islet + bone marrow, P = 0.0003, vs islet group, 5.3 +/- 1.6 in islet-alone transplants). NGF was more strongly expressed in bone marrow cells compared with islets.

Conclusion: Bone marrow cells produce NGF and promote angiogenesis. Islet co-transplantation with bone marrow is associated with improvement of islet graft function.

Figure 1

Serum nerve growth factor (NGF) data. Serum NGF levels increased post-transplantation in islet, bone marrow, and islet + bone marrow groups, while there was no increase in the sham group. There was a significant difference between bone marrow and sham group. Statistical analysis was performed by two ways repeated measurement ANOVA and significant difference was ^aP < 0.05 vs POD 0.

Figure 2

Histological findings. Kidney specimen from islet + bone marrow group stained with HE (top), Insulin (middle) and NGF (bottom) at POD 3, 7 and 14. Bone marrow cells stained strongly for NGF compared to islets at all time points (indicated by arrow). Magnification = 100 ×, Calibration bar = 1000 μm.

Figure 3

Correlation between serum NGF and blood glucose, serum insulin and GTT AUC. There were no correlation between serum NGF and other islet functional factors. R² > 0.25 and P < 0.05 is significant correlation.