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Title: Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

Abstract

Sickle cell disease is a destructive genetic disorder characterized by the formation of fibrils of deoxygenated hemoglobin, leading to the red blood cell (RBC) morphology changes that underlie the clinical manifestations of this disease. Here, using cryogenic soft X-ray tomography (SXT), we characterized the morphology of sickled RBCs in terms of volume and the number of protrusions per cell. We were able to identify statistically a relationship between the number of protrusions and the volume of the cell, which is known to correlate to the severity of sickling. This structural polymorphism allows for the classification of the stages of the sickling process. Recent studies have shown that elevated sphingosine kinase 1 (Sphk1)-mediated sphingosine 1-phosphate production contributes to sickling. Here, we further demonstrate that compound 5C, an inhibitor of Sphk1, has anti-sickling properties. Additionally, the variation in cellular morphology upon treatment suggests that this drug acts to delay the sickling process. SXT is an effective tool that can be used to identify the morphology of the sickling process and assess the effectiveness of potential therapeutics.

Authors:
 [1];  [2];  [3];  [3];  [3];  [1];  [1];  [4];  [3]; ORCiD logo [1]
  1. Baylor College of Medicine, Houston, TX (United States)
  2. Univ. of Texas Health Science Center at Houston, Houston, TX (United States)
  3. Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  4. Univ. of Texas Health Science Center at Houston, Houston, TX (United States); Univ. of Texas at Houston Graduate School of Biomedical Sciences, Houston, TX (United States); Central South Univ., Hunan (People's Republic of China)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1413703
Grant/Contract Number:
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Cell Science
Additional Journal Information:
Journal Volume: 129; Journal Issue: 18; Journal ID: ISSN 0021-9533
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Cryogenic soft X-ray tomography; Red blood cell; Sickle cell disease; Sphingosine kinase inhibitor; Red cell morphology

Citation Formats

Darrow, Michele C., Zhang, Yujin, Cinquin, Bertrand P., Smith, Elizabeth A., Boudreau, Rosanne, Rochat, Ryan H., Schmid, Michael F., Xia, Yang, Larabell, Carolyn A., and Chiu, Wah. Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography. United States: N. p., 2016. Web. doi:10.1242/jcs.189225.
Darrow, Michele C., Zhang, Yujin, Cinquin, Bertrand P., Smith, Elizabeth A., Boudreau, Rosanne, Rochat, Ryan H., Schmid, Michael F., Xia, Yang, Larabell, Carolyn A., & Chiu, Wah. Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography. United States. doi:10.1242/jcs.189225.
Darrow, Michele C., Zhang, Yujin, Cinquin, Bertrand P., Smith, Elizabeth A., Boudreau, Rosanne, Rochat, Ryan H., Schmid, Michael F., Xia, Yang, Larabell, Carolyn A., and Chiu, Wah. Tue . "Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography". United States. doi:10.1242/jcs.189225. https://www.osti.gov/servlets/purl/1413703.
@article{osti_1413703,
title = {Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography},
author = {Darrow, Michele C. and Zhang, Yujin and Cinquin, Bertrand P. and Smith, Elizabeth A. and Boudreau, Rosanne and Rochat, Ryan H. and Schmid, Michael F. and Xia, Yang and Larabell, Carolyn A. and Chiu, Wah},
abstractNote = {Sickle cell disease is a destructive genetic disorder characterized by the formation of fibrils of deoxygenated hemoglobin, leading to the red blood cell (RBC) morphology changes that underlie the clinical manifestations of this disease. Here, using cryogenic soft X-ray tomography (SXT), we characterized the morphology of sickled RBCs in terms of volume and the number of protrusions per cell. We were able to identify statistically a relationship between the number of protrusions and the volume of the cell, which is known to correlate to the severity of sickling. This structural polymorphism allows for the classification of the stages of the sickling process. Recent studies have shown that elevated sphingosine kinase 1 (Sphk1)-mediated sphingosine 1-phosphate production contributes to sickling. Here, we further demonstrate that compound 5C, an inhibitor of Sphk1, has anti-sickling properties. Additionally, the variation in cellular morphology upon treatment suggests that this drug acts to delay the sickling process. SXT is an effective tool that can be used to identify the morphology of the sickling process and assess the effectiveness of potential therapeutics.},
doi = {10.1242/jcs.189225},
journal = {Journal of Cell Science},
number = 18,
volume = 129,
place = {United States},
year = {Tue Aug 09 00:00:00 EDT 2016},
month = {Tue Aug 09 00:00:00 EDT 2016}
}

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