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Stem Cell Populations Giving Rise to Liver, Biliary Tree, and Pancreas

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Stem Cells Handbook

Abstract

Determined stem cells for liver and pancreas are present in stem cell niches, peribiliary glands (PBGs), throughout the biliary tree. PBGs are connected to intrahepatic stem cell niches, canals of Hering, and niches of committed progenitors, pancreatic duct glands. The phenotypic traits in the most primitive populations comprise both liver and pancreatic markers (transcription factors, pluripotency genes, endodermal genes), and their highest numbers are in large intrahepatic bile ducts and the hepato-pancreatic common duct. Their descendants have phenotypic traits implicating maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis from duodenum to mature cells near or in the liver or pancreas. The stem cells and lineages constitute a biological framework for hepatic and pancreatic organogenesis throughout life.

Immune- or culture-selected stem cells differentiate to mature cells when transplanted in vivo. In vitro they self-replicate vs. lineage restrict to an adult fate with wholly defined culture conditions.

Clinical trials are ongoing with stem cells transplanted via the hepatic artery into the liver of patients with various diseases and without immunosuppression. The transplants result in significant improvements in liver functions and longer life spans for patients. These findings offer hope for utilizing these stem cell populations for regenerative medicine for liver and pancreas.

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Abbreviations

AFP:

Alpha-fetoprotein

CD133:

Prominin 1

CFTR:

Cystic fibrosis transmembrane conductance regulator

CK:

Cytokeratin

C-PEP:

C-peptide

CS-PG:

Chondroitin sulfate proteoglycan

CXCR4:

CXC-chemokine receptor 4

CYP450:

Cytochrome p450

DS-PG:

Dermatan sulfate proteoglycan

EGF:

Epidermal growth factor

EpCAM:

Epithelial cell adhesion molecule (CD326)

ES cells:

Embryonic stem cells

FBS:

Fetal bovine serum

FGF:

Fibroblast growth factor

FOXA2:

Forkhead box A2

GAG:

Glycosaminoglycan

GCG:

Glucagon

GFAP:

Glial fibrillary acidic protein

HA:

Hyaluronan

hBTSC:

Human biliary tree stem cell

HDM:

Serum-free, hormonally defined medium

HGF:

Hepatocyte growth factor

hHB:

Human hepatoblast

hHpSC:

Human hepatic stem cell

HNF:

Hepatocyte nuclear factor

HP-PG:

Heparin proteoglycan

HS-PG:

Heparan sulfate proteoglycan

ICAM-1:

Intercellular adhesion molecule-1

INS:

Insulin

iPS:

Induced pluripotent stem

KM:

Kubota’s Medium

LGR5:

Leucine-rich repeat-containing G protein coupled receptor 5

MIXL1:

Mix paired-like homeobox gene (expressed in primitive streak in embryos)

MUC6:

Mucin 6, oligomeric mucus/gel-forming

NCAM:

Neural cell adhesion molecule

NGN3:

Neurogenin 3

PBG:

Peribiliary gland

PCNA:

Proliferating cell nuclear antigen

PDG:

Pancreatic duct gland

PDX1:

Pancreatic and duodenal homeobox 1

PROX1:

Prospero homeobox protein 1

SALL4:

Sal-like protein 4

SEM:

Scanning electron microscopy

SMAD:

Homolog of the Drosophila protein, mothers against decapentaplegic (MAD) and the Caenorhabditis elegans protein, SMA

SOX:

Sry-related HMG box

TEM:

Transmission electron microscopy

VCAM:

Vascular cell adhesion molecule

VEGF:

Vascular endothelial cell growth factor

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Acknowledgments

Findings from these studies have been included in patent applications belonging to Sapienza University (Rome, Italy) and/or to UNC (Chapel Hill, NC) and licensed to Vesta Therapeutics (Bethesda, MD). The authors do not have equity or a position in Vesta and are not paid consultants to the company. The authors declare no conflicts of interest. Almost all of the figures are reproduced from various publications with permission of the administrators of the journals in which they first appeared. The review was written primarily by Mark Furth and Lola Reid, with input and editing by all of the authors. All of the authors have contributed to the investigations and established the interpretations that are summarized in this review.

Authors’ note: As this book goes to press, we acknowledge the publication on “liver buds” (Takebe et al. 2013). The investigators mixed 3 different stem cell populations in culture under appropriate conditions to form the liver buds. Their findings demonstrate the importance of epithelial-mesenchymal interactions and the resulting paracrine signals in liver formation

Financial Support

UNC School of Medicine (Chapel Hill, NC). Funding derived from Vesta Therapeutics (Bethesda, MD) and from an NCI grant (CA016086).

Diabetes Research Institute (Miami, FL). Studies were funded by grants from NIH, the Juvenile Diabetes Research Foundation, ADA, and the Diabetes Research Institute Foundation. Dr. Lanzoni is supported by a scholarship dedicated to the memory of Proni Quinto and Caravita Zita, Centro Interdipartimentale per la Ricerca sul Cancro-University of Bologna, Italy.

Sapienza University Medical Center (Rome, Italy). Professor Gaudio was supported by research project grant from the University “Sapienza” of Rome and FIRB grant # RBAP10Z7FS_001 and by PRIN grant # 2009X84L84_001. Professor Alvaro was supported by FIRB grant # RBAP10Z7FS_004 and by PRIN grant # 2009X84L84_002. The study was also supported by Consorzio Interuniversitario Trapianti d’Organo, Rome, Italy.

Wake Forest School of Medicine (Winston-Salem, NC). Dr. Mark Furth is supported by WAKE FOREST INNOVATIONS of the Wake Forest School of Medicine.

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Authors and Affiliations

  1. Wake Forest Innovations, Wake Forest Baptist Medical Center, 391 Technology way, Winston Salem, NC, 27101, USA

    Mark E. Furth Ph.D.

  2. The Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, 100850, China

    Yunfang Wang M.D., Ph.D.

  3. Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 37, Viale dell’Università, 00185, Rome, Italy

    Vincenzo Cardinale M.D. & Domenico Alvaro M.D., Ph.D.

  4. Department of Health Sciences, University of Rome “Foro Italico”, Piazza Lauro de Bosis 15, 00194, Rome, Italy

    Guido Carpino M.D., Ph.D.

  5. Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 Northwest 10th Avenue, Miami, FL, 33136, USA

    Giacomo Lanzoni Ph.D., Juan Dominguez-Bendala B.Sc., M.Sc., Ph.D. & Luca Inverardi M.D.

  6. Department of Surgery, University of North Carolina School of Medicine, 101 Mason Farm Road, Glaxo Building, Room 154, Chapel Hill, NC, 27599, USA

    Cai-Bin Cui M.D., Ph.D.

  7. Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, 101 Mason Farm Road, Glaxo Building, Room 32–36, Chapel Hill, NC, 27599, USA

    Eliane Wauthier & Lola M. Reid Ph.D.

  8. Department of Surgery, University of North Carolina School of Medicine, CB#7211, 4025 Burnett-Womack Building, Chapel Hill, NC, 27599, USA

    David Gerber M.D.

  9. Department of Cell Biology and Physiology, University of North Carolina School of Medicine, 101 Mason Farm Road, Glaxo Research Building, Room 34, Chapel Hill, NC, 27599, USA

    Tsunekazu Oikawa M.D., Ph.D.

  10. Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161, Rome, Italy

    Eugenio Gaudio M.D., Ph.D.

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  1. Mark E. Furth Ph.D.
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  2. Yunfang Wang M.D., Ph.D.
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Correspondence to Lola M. Reid Ph.D. .

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  1. New York State Health Department Wadsworth Center, Albany, New York, USA

    Stewart Sell

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Furth, M.E. et al. (2013). Stem Cell Populations Giving Rise to Liver, Biliary Tree, and Pancreas. In: Sell, S. (eds) Stem Cells Handbook. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-7696-2_21

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