Abstract
RationaleStage specific embryonic antigen 1+ (SSEA1+) cells have been described as the most primitive mesenchymal progenitor cell in the bone marrow. Cardiac injury mobilizes SSEA1+ cells into the peripheral blood but their in vivo function has not been characterized.ObjectiveWe generated animals with chimeric bone marrow to determine the fate and function of bone marrow SSEA1+ cells in response to acute cardiac pressure overload.Methods and ResultsLethally irradiated mice were transplanted with normal bone marrow where the wild-type SSEA1+ cells were replaced with green fluorescent protein (GFP) SSEA1+ cells. Cardiac injury was induced by trans-aortic constriction (TAC). We identified significant GFP+ cell engraftment into the myocardium after TAC. Bone marrow GFP+ SSEA1 derived cells acquired markers of endothelial lineage, but did not express markers of c-kit+ cardiac progenitor cells. The function of bone marrow SSEA1+ cells after TAC was determined by transplanting lethally irradiated mice with bone marrow depleted of SSEA1+ cells (SSEA1-BM). The cardiac function of SSEA1-BM mice declined at a greater rate after TAC compared to their complete bone marrow transplant counterparts and was associated with decreased bone marrow cell engraftment and greater vessel rarefication in the myocardium.ConclusionsThese results provide evidence for the recruitment of endogenous bone marrow SSEA1+ cells to the myocardium after TAC. We demonstrate that, in vivo, bone marrow SSEA1+ cells have the differentiation potential to acquire endothelial lineage markers. We also show that bone marrow SSEA1+ deficiency is associated with a reduced compensatory capacity to cardiac pressure overload, suggesting their importance in cardiac homeostasis. These data demonstrate that bone marrow SSEA1+ cells are critical for sustaining vascular density and cardiac repair to pressure overload.
Highlights
Recent evidence suggests a role for a systemic stem cell response in the cardiac repair process [1,2], including a local cardiac stem cell (CSC) response [3,4,5]
Significantly more green fluorescent protein (GFP)+ cells than Stage specific embryonic antigen 1 (SSEA1)+ cells were found in the bone marrow of sham and trans-aortic constriction (TAC) animals (SSEA1+ cells: 0.18 ± 0.03% of total BM, GFP+: 0.50 ±0.13% of total BM, P = 0.05)
We found an increase in the number of SSEA1+ cells 7 days post-TAC in the heart (Sham 0.08 ± 0.01% of viable cells, TAC 0.24 ± 0.11% of viable cells, P = 0.02, Figure 1D)
Summary
Recent evidence suggests a role for a systemic stem cell response in the cardiac repair process [1,2], including a local cardiac stem cell (CSC) response [3,4,5]. The exact bone marrow stem cell populations involved and their specific roles in cardiac repair remain to be defined. Populations of SSEA1+ cells have recently been identified in the adult, including in the bone marrow, spleen, heart, and brain [2,11,12]. Bone marrow SSEA1+ cells have been described as the most primitive mesenchymal progenitor cell with the potential to differentiate into all three germ layers in vitro [13]. SSEA1 expression has been associated with a specific multipotent bone marrow stem cell population known as very small embryonic-like stem cells (VSEL). VSEL are identified as sca-1, oct-4, and CXCR4 positive [14]
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