Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG) protein in fulminant type 1 diabetes.
BACKGROUND
Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear.


METHODS
The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans.


RESULTS
Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells.


CONCLUSIONS
The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Kaoru
K
Aida
Department of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Sei
S
Saitoh
Department of Nursing, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Yoriko
Y
Nishida
Section of Functional Morphology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Saseho, Nagasaki, Japan.
Sadanori
S
Yokota
Department of Anatomy and Molecular Histology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Shinichi
S
Ohno
Department of Computer Science, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Xiayang
X
Mao
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Daiichiro
D
Akiyama
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Shoichiro
S
Tanaka
Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical School, Moroyama, Saitama, Japan.
Takuya
T
Awata
Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan.
Akira
A
Shimada
Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan.
Youichi
Y
Oikawa
Department of Laboratory Medicine, Fukushima Medical University, Fukushima, Fukushima, Japan.
Hiroki
H
Shimura
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Fumihiko
F
Furuya
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Soichi
S
Takizawa
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Masashi
M
Ichijo
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Sayaka
S
Ichijo
Department of Surgery I, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Jun
J
Itakura
Department of Surgery I, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Hideki
H
Fujii
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Akinori
A
Hashiguchi
Department of Biochemistry, Nara Medical University, Kashihara, Wakayama, Japan.
Shin
S
Takasawa
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Toyoshi
T
Endo
Department of Internal Medicine III, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
Tetsuro
T
Kobayashi
D000293:Adolescent; D000328:Adult; D000368:Aged; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology*; D051847:Lithostathine / Q000378:metabolism*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*
D051847:Lithostathine; C497617:REG1A protein, human