Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells.
A key question in diabetes research is whether new β-cells can be derived from endogenous, nonendocrine cells. The potential for pancreatic ductal cells to convert into β-cells is a highly debated issue. To date, it remains unclear what anatomical process would result in duct-derived cells coming to exist within preexisting islets. We used a whole-mount technique to directly visualize the pancreatic ductal network in young wild-type mice, young humans, and wild-type and transgenic mice after partial pancreatectomy. Pancreatic ductal networks, originating from the main ductal tree, were found to reside deep within islets in young mice and humans but not in mature mice or humans. These networks were also not present in normal adult mice after partial pancreatectomy, but TGF-β receptor mutant mice demonstrated formation of these intraislet duct structures after partial pancreatectomy. Genetic and viral lineage tracings were used to determine whether endocrine cells were derived from pancreatic ducts. Lineage tracing confirmed that pancreatic ductal cells can typically convert into new β-cells in normal young developing mice as well as in adult TGF-β signaling mutant mice after partial pancreatectomy. Here the direct visual evidence of ducts growing into islets, along with lineage tracing, not only represents strong evidence for duct cells giving rise to β-cells in the postnatal pancreas but also importantly implicates TGF-β signaling in this process.
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Yousef
Y
El-Gohary
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
John
J
Wiersch
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Sidhartha
S
Tulachan
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Xiangwei
X
Xiao
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Ping
P
Guo
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Christopher
C
Rymer
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Shane
S
Fischbach
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Krishna
K
Prasadan
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Chiyo
C
Shiota
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Iljana
I
Gaffar
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Zewen
Z
Song
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Csaba
C
Galambos
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
Farzad
F
Esni
Departments of Surgery (Y.E.-G., J.W., X.X., P.G., K.P., C.S., I.G., Z.S., F.E., G.K.G.) and Pediatrics (C.R.), Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224; Department of Surgery (Y.E.-G.), Stony Brook University Medical Center, Stony Brook, New York 11794; Department of Surgery (J.W.), University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229; Section of Gastroenterology/Hepatology (S.T.), Georgia Regents University, Augusta, Georgia 30912; Division of Biology and Medicine (S.F.), Brown University, Providence, Rhode Island 02912; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central South University, Yuelu, Changsha, Hunan 410013, China; and Department of Pathology and Laboratory Medicine (C.G.), Children's Hospital Colorado, Aurora, Colorado 80045.
George K
GK
Gittes
D000293:Adolescent; D000367:Age Factors; D000818:Animals; D002102:Cadaver; D054338:Cell Transdifferentiation; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology; D007515:Islets of Langerhans / Q000166:cytology* / Q000254:growth & development / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010180:Pancreatectomy; D010183:Pancreatic Ducts / Q000166:cytology* / Q000254:growth & development / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D000097573:Red Fluorescent Protein
D007328:Insulin; D008164:Luminescent Proteins; D050505:Mutant Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D000097573:Red Fluorescent Protein