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. 2018 Aug;11(4):274-284.
doi: 10.1007/s12265-017-9772-y. Epub 2018 Feb 21.

SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells

Andrew B Goldstone  1 , Cassandra E Burnett  2 , Jeffery E Cohen  1 , Michael J Paulsen  1 , Anahita Eskandari  1 , Bryan E Edwards  1 , Arnar B Ingason  1 , Amanda N Steele  1 , Jay B Patel  1 , John W MacArthur  1 , Judith A Shizuru  2 , Y Joseph Woo  3
Affiliations

SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells

Andrew B Goldstone et al. J Cardiovasc Transl Res. 2018 Aug.

Abstract

Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.

Keywords: Angiogenesis; Bone marrow; Cell fusion; Myocardial infarction; Regeneration.

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Figures

Figure 1
Figure 1
Exogenous SDF enhances post-infarction myocardial function and increases border zone vessel density. (A) Left ventricular ejection fraction (B) and fractional shortening (FS) measured by transthoracic echocardiography and stratified by treatment group. (C) Comparison of relative Von Willebrand factor expression in the infarct border zone between SDF-treated and PBS-treated groups. (D, E) Representative images comparing infarct border zone capillary density between SDF-treated and PBS-treated groups. Scale bar, 100 μm.
Figure 2
Figure 2
Lineage-tracing model for tracking the fate of circulating bone marrow cells within the heart. (A) Schematic of experimental model for fate tracking. (B) Percentages of recipient-donor chimerism after bone marrow transplant stratified by hematopoietic cell type at 6 weeks. (C) Representative bone marrow smear of transplanted recipient. (D) Endothelial progenitor cells from transplanted recipients.
Figure 3
Figure 3
Bone marrow cells adopt endothelial cell fates within the heart. (A) Flow cytometry analysis of cardiac associated cells demonstrating the DsRed+/CD31+ and DsRed+/CD45+ populations. (B) Percentage of CD31+ cells in MI injured and sham surgery hearts. (C) Percentage of bone marrow-derived CD31+ cells in MI injured and sham surgery hearts. (D) Percentage of CD31+ cells due to fusion (GFP+/DsRed+) or de novo formation (GFP-/DsRed+). (E, F) Representative images of bone marrow-derived endothelial cells that co-express Von Willebrand factor and DsRed in boarder zone and remote regions. Scale bar, 100 μm.
Figure 4
Figure 4
Bone marrow cells adopt cardiomyocyte fates within the heart. (A) Flow cytometry analysis demonstrating the DsRed+/troponin+ population. (B) Percentage of troponin+ cells in MI injured and sham surgery hearts. (C) Percentage of bone marrow-derived troponin+ cells in MI injured and sham surgery hearts. (D) Percentage of troponin+ cells due to fusion (GFP+/DsRed+) or de novo formation (GFP−/DsRed+). (E) Bone marrow-derived troponin+ cells outside of infarct area that co-express DsRed and troponin. Scale bar, 25 μm. (F) Sorted cardiomyocytes. The superior cell expresses troponin, DsRed and GFP and likely arose from cell fusion. The inferior cell only expresses troponin and DsRed and likely arose from de novo generation. Scale bar, 50 μm.
Figure 5
Figure 5
The pro-angiogenic effect of SDF is not due to an alteration in the direct contribution of circulating bone marrow cells. (A) The percent of CD31+ cells stratified by treatment assignment. (B) Comparison of the percent of CD31+ cells that are derived from bone marrow cells between SDF-treated and PBS-treated groups. (C) Comparison of the percent of troponin+ cells that are derived from bone marrow cells between SDF-treated and PBS-treated groups.
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