Abstract
Background: The beneficial impact of mesenchymal stem cells (MSC) on both acute and chronic liver diseases has been confirmed, although the molecular mechanisms behind it remain elusive. We aim to identify factors secreted by undifferentiated and hepatocytic differentiated MSC in vitro in order to delineate liver repair pathways potentially targeted by MSC. Methods: Secreted factors were determined by protein arrays and related pathways identified by biomathematical analyses. Results: MSC from adipose tissue and bone marrow expressed a similar pattern of surface markers. After hepatocytic differentiation, CD54 (intercellular adhesion molecule 1, ICAM-1) increased and CD166 (activated leukocyte cell adhesion molecule, ALCAM) decreased. MSC secreted different factors before and after differentiation. These comprised cytokines involved in innate immunity and growth factors regulating liver regeneration. Pathway analysis revealed cytokine-cytokine receptor interactions, chemokine signalling pathways, the complement and coagulation cascades as well as the Januskinase-signal transducers and activators of transcription (JAK-STAT) and nucleotide-binding oligomerization domain-like receptor (NOD-like receptor) signalling pathways as relevant networks. Relationships to transforming growth factor β (TGF-β) and hypoxia-inducible factor 1-α (HIF1-α) signalling seemed also relevant. Conclusion: MSC secreted proteins, which differed depending on cell source and degree of differentiation. The factors might address inflammatory and growth factor pathways as well as chemo-attraction and innate immunity. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration.
Highlights
The biological features of mesenchymal stem cells (MSC) make them feasible candidates for cellular therapy for a variety of diseases, e.g., acute kidney injury, brain repair after stroke, colitis [1,2,3,4,5,6], and acute and chronic liver diseases [7,8,9,10,11,12,13,14]
transforming growth factor β (TGF-β), which does display beneficial and deleterious actions in the liver like initiation of fibrosis by the activation of hepatic stellate cells, is involved in multiple pathways comprising the JAK-STAT, Jun N-terminal kinase (JNK) and mitogen-activated protein kinases (MAPK) pathways [33,34] and their crosstalk with cyto- and chemokine pathways mediated by fibroblast growth factors (FGFs) [35], CC chemokine ligands (CCLs) [36], interleukines (ILs) [37] and brain-derived neurotrophic factor (BDNF) [38]
The compilation of factors produced by human MSC from different tissue sources demonstrated that the manipulation of the cells like hepatocytic differentiation dramatically changed the pattern of the secreted proteins, both qualitatively and quantitatively
Summary
The biological features of mesenchymal stem cells (MSC) make them feasible candidates for cellular therapy for a variety of diseases, e.g., acute kidney injury, brain repair after stroke, colitis [1,2,3,4,5,6], and acute and chronic liver diseases [7,8,9,10,11,12,13,14]. TGF-β, which does display beneficial and deleterious actions in the liver like initiation of fibrosis by the activation of hepatic stellate cells, is involved in multiple pathways comprising the JAK-STAT, JNK and mitogen-activated protein kinases (MAPK) pathways [33,34] and their crosstalk with cyto- and chemokine pathways mediated by fibroblast growth factors (FGFs) [35], CC chemokine ligands (CCLs) [36], interleukines (ILs) [37] and brain-derived neurotrophic factor (BDNF) [38] It is of ultimate importance before clinical application of MSC to characterise their potential mode of action in respect of their paracrine response to a given liver disease. Since these are prone to dysregulation in most liver diseases, MSC release hepatotropic factors, potentially supporting liver regeneration
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