Bone marrow (BM) transplantation promotes beta-cell regeneration after acute injury through BM cell mobilization.
There is controversy regarding the roles of bone marrow (BM)-derived cells in pancreatic beta-cell regeneration. To examine these roles in vivo, mice were treated with streptozotocin (STZ), followed by bone marrow transplantation (BMT; lethal irradiation and subsequent BM cell infusion) from green fluorescence protein transgenic mice. BMT improved STZ-induced hyperglycemia, nearly normalizing glucose levels, with partially restored pancreatic islet number and size, whereas simple BM cell infusion without preirradiation had no effects. In post-BMT mice, most islets were located near pancreatic ducts and substantial numbers of bromodeoxyuridine-positive cells were detected in islets and ducts. Importantly, green fluorescence protein-positive, i.e. BM-derived, cells were detected around islets and were CD45 positive but not insulin positive. Then to examine whether BM-derived cell mobilization contributes to this process, we used Nos3(-/-) mice as a model of impaired BM-derived cell mobilization. In streptozotocin-treated Nos3(-/-) mice, the effects of BMT on blood glucose, islet number, bromodeoxyuridine-positive cells in islets, and CD45-positive cells around islets were much smaller than those in streptozotocin-treated Nos3(+/+) controls. A series of BMT experiments using Nos3(+/+) and Nos3(-/-) mice showed hyperglycemia-improving effects of BMT to correlate inversely with the severity of myelosuppression and delay of peripheral white blood cell recovery. Thus, mobilization of BM-derived cells is critical for BMT-induced beta-cell regeneration after injury. The present results suggest that homing of donor BM-derived cells in BM and subsequent mobilization into the injured periphery are required for BMT-induced regeneration of recipient pancreatic beta-cells.
Hasegawa
Yutaka
Y
Division of Advanced Therapeutics for Metabolic Diseases, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan.
Ogihara
Takehide
T
Yamada
Tetsuya
T
Ishigaki
Yasushi
Y
Imai
Junta
J
Uno
Kenji
K
Gao
Junhong
J
Kaneko
Keizo
K
Ishihara
Hisamitsu
H
Sasano
Hironobu
H
Nakauchi
Hiromitsu
H
Oka
Yoshitomo
Y
Katagiri
Hideki
H
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000628:therapy*; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006943:Hyperglycemia / Q000473:pathology / Q000628:therapy; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D010183:Pancreatic Ducts; D012038:Regeneration; D014916:Whole-Body Irradiation
D007328:Insulin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse