Novel Role for Bioactive Lipids in Mobilization of Bone Marrow Stem Cells During Myocardial Ischemia: Sphingosine-1 Phosphate (S1P) As Potential Therapeutic Target
Authors: Latif Ahmed Abdel , Karapetyan Anush K. , Klyachkin Yuri , Sunkara Manjula , Smyth Susan , Ratajczak Mariusz Z , Morris Andrew J. 
Published: October 2019

Abstract
Abstract 1911

Background:
Bone marrow (BM) contains a variety of stem cells, including mobile pool of hematopoietic stem cells and non-hematopoietic stem cells and acute myocardial infarction (AMI) triggers mobilization of BM-derived stem cells (BMSCs) through poorly understood processes. Recently we have postulated a major role for bioactive lipids such as sphingosine-1 phosphate (S1P) in G-CSF- and AMD3100-induced mobilization of hematopoietic stem cells (HSCs) into peripheral blood (PB) (Leukemia 2010;24:976–85).

Hypothesis:
We hypothesized that S1P could also play a role in mobilization of BMSCs in patients during tissue and organ injury as seen for example in patients with AMI.

Methods:
Peripheral blood (PB) samples from matched controls and patients presenting with ST-elevation myocardial infarction (STEMI) were examined i) by employing FACS for a number of circulating in PB lineage negative (Lin-)/CD45-/CD34+ and CD133+ and CXCR4+ BMSCs, ii) PB level of S1P by employing mass spectrometry, iii) SDF-1 level by ELISA and finally iv) BMSCs were tested in Transwell migration assays for their chemotactic responsiveness to S1P gradient in plasma from STEMI patients.

Results:
Plasma S1P levels were highest within 6 hours of AMI presentation 0.31 ± 0.02 μM and declined to 0.14 ± 0.02 μM in controls (P < 0.05 for 6 hours vs. controls). The elevation of plasma S1P corresponded with complement cascade (CC) activation and higher levels of C5b-C9 membrane attack complex (MAC) complex in the plasma. The largest reservoir of S1P in whole blood was red blood cells (RBCs) and incubation of RBCs with activated complement initiated the release of S1P. Elevated plasma S1P levels was paralleled by early significant increase in circulating lineage negative (Lin-)/CD45-/CD34+, CD133+ and CXCR4+ BMSCs (P < 0.01 vs. controls). Plasma obtained from STEMI patients in the early phases following acute injury stimulated the migration of human BM-derived Lin-/CXCR4+ and Lin-/CD34+ BMSCs in chemotaxis assays (7–8-fold increase vs. vehicle, P < 0.05), this effect was blunted by charcoal stripping of the plasma (CSP) and was further inhibited by the specific S1P receptor type 1 (S1P1) antagonists W146 (10 μM) and VPC20139 (10 μM). At the same time to our surprise we did not observed significant chemotactic relevant changes in SDF-1 level in PB plasma.

Conclusion:
This is the first human study to suggest that elevated S1P level in PB early in the course of AMI mobilizes BMSCs. Furthermore, we demonstrate for the first time that the release of hematopoietic and non-hematopoietic BMSCs into PB correlates in AMI patients with activation of CC and generation of MAC, that may release S1P from erythrocytes and platelets. We postulate that based on these results future studies examining the therapeutic manipulation of S1P and its receptors for myocardial regeneration are warranted.

Disclosures:
No relevant conflicts of interest to declare.