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Recapitulating pancreatic cell–cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy

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Abstract

Over the past few years, extensive efforts have been made to generate in-vitro pancreatic micro-tissue, for disease modeling or cell replacement approaches in pancreatic related diseases such as diabetes mellitus. To obtain these goals, a closer look at the diverse cells participating in pancreatic development is necessary. Five major non-epithelial pancreatic (pN-Epi) cell populations namely, pancreatic endothelium, mesothelium, neural crests, pericytes, and stellate cells exist in pancreas throughout its development, and they are hypothesized to be endogenous inducers of the development. In this review, we discuss different pN-Epi cells migrating to and existing within the pancreas and their diverse effects on pancreatic epithelium during organ development mediated via associated signaling pathways, soluble factors or mechanical cell–cell interactions. In-vivo and in-vitro experiments, with a focus on N-Epi cells’ impact on pancreas endocrine development, have also been considered. Pluripotent stem cell technology and multicellular three-dimensional organoids as new approaches to generate pancreatic micro-tissues have also been discussed. Main challenges for reaching a detailed understanding of the role of pN-Epi cells in pancreas development in utilizing for in-vitro recapitulation have been summarized. Finally, various novel and innovative large-scale bioengineering approaches which may help to recapitulate cell–cell interactions and are crucial for generation of large-scale in-vitro multicellular pancreatic micro-tissues, are discussed.

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Notes

  1. a Lipophilic cationic indocarbocyanine fluorescent dye for membrane staining.

  2. A cell-surface chondroitin sulfate proteoglycan.

  3. The epithelium lining the surface layer of the embryonic mesoderm.

  4. Magnetic levitation method (MLM) applies growing 3D tissue by inducing cells treated with magnetic nanoparticle assemblies in spatially varying magnetic fields using neodymium magnetic drivers and promoting cell–cell interactions by levitating the cells up to the air/liquid interface of a standard petri dish.

Abbreviations

2D:

Two-dimensional

3D:

Three-dimensional

α-SMA:

Alpha-smooth muscle actin

AAT:

Alpha-1 antitrypsin

Ang-1:

Angiopoietin

BM-MSC:

Bone marrow-mesenchymal stem cells

BMP4:

Bone morphogenetic protein 4

CF:

Cystic fibrosis

CFTR:

Cystic fibrosis transmembrane conductance regulator

DM:

Diabetes mellitus

DKK1:

Dickkopf-related protein 1

DPC:

Days post-conception

EB:

Embryoid bodies

E:

Embryonic day

EC:

Endothelial cell

ECM:

Extra cellular matrix

EGFL7:

Epidermal growth factor‐like domain 7

EPC:

Endothelial progenitor cell

eNOS:

Endothelial nitric-oxide synthase

FAK:

Focal adhesion kinase

FGF10:

Fibroblast growth factor 10

FOXD3:

Forkhead Box D3

GDNF:

Glial cell-derived neurotrophic factor

GFP:

Green fluorescent protein

GLUT2:

Glucose transporter 2

GP2:

Glycoprotein 2

GSIS:

Glucose -stimulated insulin secretion

hESC:

Human embryonic stem cell

HGF:

Hepatocyte growth factor

hiPSC:

Human induced pluripotent stem cell

hPSC:

Human pluripotent stem cell

HOX:

Homeobox

HUVEC:

Human umbilical vein endothelial cell

IGF:

Insulin growth factor

IL-6:

Interleukin-6

IRS2:

Insulin receptor substrate-2

ISL-1:

Insulin gene enhancer protein ISL-1

LAMA2:

α2 Laminins

LGALS1:

Galectin 1

MAFA:

Musculoaponeurotic fibrosarcoma oncogene family A.

mESC:

Mouse embryonic stem cell

MIDY:

Mutant insulin-gene-induced diabetes of youth

MIN6:

Mouse insulinoma 6

MMP:

Metalloproteinases

MPCs:

Multipotent progenitor cells

MSCs:

Mesenchymal stem cells

NC:

Neural crest

NG2:

Neural-glial Antigen 2

NGN3:

Neurogenin3

NKX3.2:

NK3 Homeobox 2 /NKX2.2: NK2 Homeobox 2 /NKX6.1: NK6 Homeobox 1

PDAC:

Pancreatic ductal adenocarcinoma

PAX3:

Paired box gene 3

PHOX2B:

Paired-like homeobox 2b

PECAM1:

Platelet and endothelial cell adhesion molecule 1

PEG:

Poly Ethylene Glycol

PES/PBP:

Poly ether sulfone/poly vinyl pyrrolidone

PBX1:

Pre-B-cell leukemia transcription factor 1

PDX1:

Pancreas-duodenum homeobox protein1

PDGF:

Platelet-derived growth factor

PDGFRβ:

Platelet-derived growth factor receptor-beta

PGA:

Poly glycolic acid

PTF1a:

Pancreas transcription factor 1 subunit alpha

pN-Epi:

Pancreatic non-epithelial

RAS:

Renin–angiotensin system

RHMVEC:

Rat heart microvascular endothelial cell

S1P:

Sphingosine-1-phosphate

SC-β CELLS:

Stem cell-derived β-cells

SDC4:

Syndecan4

SFRP3:

Secreted frizzled-related protein 3

SOX9/10:

SRY-Box 9/10

STZ:

Streptozotocin

SynCAM:

Synaptic cell adhesion molecule/CADM-1

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

TCF7L2:

Transcription factor 7 like 2

TGFβ:

Transforming growth factor β

Tie-2:

Tyrosine-protein kinase receptor Tie-2

TIMP-1:

TIMP metallopeptidase inhibitor 1

TF:

Transcription factor

TFAP2α:

Transcription factor AP-2 alpha

Vcan:

Versican

VEGF:

Vascular endothelial growth factor

vSMC:

Vascular smooth muscle cell

WPC:

Weeks post-conception

WNT:

Wingless

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Acknowledgements

This study was funded by Royan Institute for Stem Cell Biology and Technology (RI-SCBT) and Royan’s Lotus Charity Investment Foundation.

Funding

This study was funded by Royan Institute for Stem Cell Biology and Technology (RI-SCBT) and the Lotus Charity Investment Foundation, Royan Institute.

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Author notes

  1. Zahra Ghezelayagh and Mahsa Zabihi contributed equally to this work.

Authors and Affiliations

  1. Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran

    Zahra Ghezelayagh & Zeinab Ghezelayagh

  2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Zahra Ghezelayagh, Mahsa Zabihi & Yaser Tahamtani

  3. Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran

    Mahsa Zabihi

  4. Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Mohammad Kazemi Ashtiani

  5. Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Zeinab Ghezelayagh

  6. Diabetes Research Group, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

    Francis C. Lynn

  7. Department of Surgery and School of Biomedical Engineering , University of British Columbia, Vancouver, BC, Canada

    Francis C. Lynn

  8. Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Yaser Tahamtani

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  1. Zahra Ghezelayagh
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  4. Zeinab Ghezelayagh
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  5. Francis C. Lynn
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Contributions

The conception and design of the study was done by [YT]. Administrative support was done by [FCL]. The first draft of the manuscript was written by [ZG, MZ, MKA, and ZG], and all authors commented on previous version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yaser Tahamtani.

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Ghezelayagh, Z., Zabihi, M., Kazemi Ashtiani, M. et al. Recapitulating pancreatic cell–cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy. Cell. Mol. Life Sci. 78, 7107–7132 (2021). https://doi.org/10.1007/s00018-021-03951-2

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