Human Blood Serum Induces p38-MAPK- and Hsp27-Dependent Migration Dynamics of Adult Human Cardiac Stem Cells: Single-Cell Analysis via a Microfluidic-Based Cultivation Platform.

Anna L. Höving,Alexander Grünberger,Julian Schmitz,Cornelius Knabbe,Kazuko E. Schmidt,Christian Kaltschmidt,Barbara Kaltschmidt,Johannes F. W. Greiner

doi:10.3390/biology10080708

Abstract

Simple SummaryAdult human stem cells possess the ability to contribute to endogenous regeneration processes of injured tissue by migrating to specific locations. For stem cell-based clinical applications it is highly important to gain knowledge about the migration behavior of adult human stem cells and the underlying molecular mechanisms of this ability. Human blood serum has been shown to have beneficial effects on other regenerative capacities of adult human stem cells. Within this study we tested the effect of human blood serum on the migration behavior of stem cells from the human heart. We used a microfluidic cultivation device, which allowed us to monitor the living cells and their movement behavior in real time. After addition of human blood serum, the heart stem cells increased their speed of movement and covered distance. Further, we observed that this effect could be diminished by inhibition of a specific kinase, p38-MAPK. Thus, our data suggest beneficial effects of human blood serum on adult human heart stem cells dependent on p38-MAPK. Our study contributes to a deeper understanding of the dynamics of stem cell migration and introduces a new platform to monitor stem cell movement in real time.Migratory capabilities of adult human stem cells are vital for assuring endogenous tissue regeneration and stem cell-based clinical applications. Although human blood serum has been shown to be beneficial for cell migration and proliferation, little is known about its impact on the migratory behavior of cardiac stem cells and underlying signaling pathways. Within this study, we investigated the effects of human blood serum on primary human cardiac stem cells (hCSCs) from the adult heart auricle. On a technical level, we took advantage of a microfluidic cultivation platform, which allowed us to characterize cell morphologies and track migration of single hCSCs via live cell imaging over a period of up to 48 h. Our findings showed a significantly increased migration distance and speed of hCSCs after treatment with human serum compared to control. Exposure of blood serum-stimulated hCSCs to the p38 mitogen-activated protein kinase (p38-MAPK) inhibitor SB239063 resulted in significantly decreased migration. Moreover, we revealed increased phosphorylation of heat shock protein 27 (Hsp27) upon serum treatment, which was diminished by p38-MAPK-inhibition. In summary, we demonstrate human blood serum as a strong inducer of adult human cardiac stem cell migration dependent on p38-MAPK/Hsp27-signalling. Our findings further emphasize the great potential of microfluidic cultivation devices for assessing spatio-temporal migration dynamics of adult human stem cells on a single-cell level.

Highlights

Adult human stem cells (ASCs) can be found in various tissues of the human body where they remain as quiescent cells in their respective niches and upon activation contribute to tissue renewal and regeneration [1]
This study demonstrated a beneficial effect of human blood serum on the migration behavior of an adult human cardiac stem cell population in a p38MAPK/phospho-heat shock protein 27 (Hsp27)-dependent manner
We further provided a microfluidic-based cultivation method facilitating the measurement of primary human stem cell migration

Summary

Introduction

Adult human stem cells (ASCs) can be found in various tissues of the human body where they remain as quiescent cells in their respective niches and upon activation contribute to tissue renewal and regeneration [1]. The underlying mechanisms of this process are well described, and migration requires a deformation of the cell shape, which is achieved by reorganization of the actin cytoskeleton. A highly orchestrated cascade of actin polymerization drives the formation of protrusions and the adhesion to a substrate or extracellular matrix (ECM) at the leading zone of cell movement [3]. Various stimuli have been identified that induce or inhibit migratory behavior in diverse cell populations. As well as mechanical factors like shear stress, matrix stiffness or mechanical strain [4,5,6,7], a range of chemokines, cytokines and growth factors is involved in the regulation of stem cell migration behavior [8]

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