Cell and Tissue Research

, Volume 354, Issue 3, pp 647–669 | Cite as

Innovations in studying in vivo cell behavior and pharmacology in complex tissues – microvascular endothelial cells in the spotlight

  • Elise Langenkamp
  • Jan A. A. M. Kamps
  • Michal Mrug
  • Elisabeth Verpoorte
  • Yilmaz Niyaz
  • Peter Horvatovich
  • Rainer Bischoff
  • Harry Struijker-Boudier
  • Grietje Molema
Review

Abstract

Many studies on the molecular control underlying normal cell behavior and cellular responses to disease stimuli and pharmacological intervention are conducted in single-cell culture systems, while the read-out of cellular engagement in disease and responsiveness to drugs in vivo is often based on overall tissue responses. As the majority of drugs under development aim to specifically interact with molecular targets in subsets of cells in complex tissues, this approach poses a major experimental discrepancy that prevents successful development of new therapeutics. In this review, we address the shortcomings of the use of artificial (single) cell systems and of whole tissue analyses in creating a better understanding of cell engagement in disease and of the true effects of drugs. We focus on microvascular endothelial cells that actively engage in a wide range of physiological and pathological processes. We propose a new strategy in which in vivo molecular control of cells is studied directly in the diseased endothelium instead of at a (far) distance from the site where drugs have to act, thereby accounting for tissue-controlled cell responses. The strategy uses laser microdissection-based enrichment of microvascular endothelium which, when combined with transcriptome and (phospho)proteome analyses, provides a factual view on their status in their complex microenvironment. Combining this with miniaturized sample handling using microfluidic devices enables handling the minute sample input that results from this strategy. The multidisciplinary approach proposed will enable compartmentalized analysis of cell behavior and drug effects in complex tissue to become widely implemented in daily biomedical research and drug development practice.

Keywords

(Endothelial) cell behavior Pharmacology In vivo Laser microdissection Omics technology 

Abbreviations

ACE

Angiotensin converting enzyme

ALK

Activin receptor-like Kinase

BAD

B-cell lymphoma 2-associated death promoter

BBB

Blood–brain barrier

Bcl2

B-cell lymphoma 2

COX

Cyclooxygenase

ECM

Extracellular matrix

ERK

Extracellular signal-regulated kinase

FGF

Fibroblast growth factor

FT-MS

Fourier transform mass spectrometry

HIF

Hypoxia-inducible factor

HPLC

High performance liquid chromatography

ICAM

Intercellular adhesion molecule

IL-1

Interleukin-1

LDA

Low-density array

LDH

Lactase dehydrogenase

LFA

Leukocyte function antigen

lncRNA

Long non-coding RNA

LoaC

Lab on a chip

LPS

Lipopolysaccharide

MALDI-TOF (MS)

Matrix-assisted laser desorption/ionization-time of flight (mass spectometry)

MAPK

Mitogen activated protein kinase

NFκB

Nuclear factor κ-B

NGS

Next generation sequencing

NOS

Nitric oxide synthase

PAGE

Polyacrylamide gel electrophoresis

PDGF

Platelet-derived growth factor

PI3K

Phosphoinositide 3-kinase

PKB

Protein kinase B

PKC

Protein kinase C

PV-1

Plasmalemma vesicle-associated protein-1

RCC

Renal cell carcinoma

RT-PCR

Reverse transcriptase-polymerase chain reaction

SELDI-TOF (MS)

Surface-enhanced laser desorption/ionization-time of flight (mass spectometry)

SRM

Single reaction monitoring

TGF

Transforming growth factor

TNF(R)

Tumor necrosis factor (receptor)

tPA

Tissue-type plasminogen activator

uPA

Urokinase-type plasminogen activator

VCAM

Vascular cell adhesion molecule

VE-cadherin

Vascular endothelial cadherin

VEGF(R)

Vascular endothelial growth factor (receptor)

VE-PTP

Vascular endothelial protein tyrosine phosphatase

VLA

Very late antigen

VVO

Vesiculo-vacuolar organelle

ZO

Zonal occludens

Notes

Acknowledgments

We are indebted to Dr. Geny M.M. Groothuis for fruitful discussion on species difference and drug metabolism. Research by G.M. and M.M. has in part been funded by the Genzyme Renal Innovations Program.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elise Langenkamp
    • 1
    • 8
  • Jan A. A. M. Kamps
    • 1
  • Michal Mrug
    • 2
    • 3
  • Elisabeth Verpoorte
    • 4
  • Yilmaz Niyaz
    • 5
  • Peter Horvatovich
    • 6
  • Rainer Bischoff
    • 6
  • Harry Struijker-Boudier
    • 7
  • Grietje Molema
    • 1
    • 9
  1. 1.University Medical Center Groningen, Department of Pathology and Medical Biology, Medical Biology sectionUniversity of GroningenGroningenThe Netherlands
  2. 2.Division of Nephrology, Department of Medicine, Nephrology Research and Training CenterUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Department of Veterans Affairs Medical CenterBirminghamUSA
  4. 4.Groningen Research Institute of Pharmacy, Pharmaceutical AnalysisUniversity of GroningenGroningenThe Netherlands
  5. 5.Carl Zeiss Microscopy GmbHJenaGermany
  6. 6.Groningen Research Institute of Pharmacy, Analytical BiochemistryUniversity of GroningenGroningenThe Netherlands
  7. 7.Department of Pharmacology and ToxicologyMaastricht UniversityMaastrichtThe Netherlands
  8. 8.Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
  9. 9.University Medical Center GroningenGroningenThe Netherlands

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