Abstract
Stem/progenitor cells from multiple tissues have been isolated based on enhanced activity of cytosolic aldehyde dehydrogenase (ALDH) enzyme. ALDH activity has emerged as a reliable marker for stem/progenitor cells, such that ALDHbright/high cells from multiple tissues have been shown to possess enhanced stemness properties (self-renewal and multipotency). So far though, not much is known about ALDH activity in specific fetal organs. In this study, we sought to analyze the presence and activity of the ALDH enzyme in the stem cell antigen-1-positive (Sca-1+) cells of fetal human heart. Biochemical assays showed that a subpopulation of Sca-1+ cells (15%) possess significantly high ALDH1 activity. This subpopulation showed increased expression of self-renewal markers compared to the ALDHlow fraction. The ALDHhigh fraction also exhibited significant increase in proliferation and pro-survival gene expression. In addition, only the ALDHhigh and not the ALDHlow fraction could give rise to all the cell types of the original population, demonstrating multipotency. ALDHhigh cells showed increased resistance against aldehyde challenge compared to ALDHlow cells. These results indicate that ALDHhigh subpopulation of the cultured human fetal cells has enhanced self-renewal, multipotency, high proliferation, and survival, indicating that this might represent a primitive stem cell population within the fetal human heart.
Highlights
Stem cell antigen-1-positive (Sca-1+) cells from adult mouse hearts were shown to demonstrate increased proliferation and stemness along with potential to differentiate into multiple cardiac cell lineages [1,2,3]
While the ALDHlow Sca-1+ cells could only give rise to ALDHlow subpopulation (>97%; P value < 0.05) (Figure 5), the ALDHhigh Sca-1+ cells recapitulated the original population by giving rise to both the ALDHhigh and ALDHlow populations, in addition to maintaining a high percentage of the cells with ALDHhigh phenotype. This was consistently observed for multiple samples, and this observation held true even after 2-3 weeks of culture. This is the first study which identifies a distinct subpopulation of cells in the fetal human heart having high aldehyde dehydrogenase (ALDH) activity and possessing enhanced potency for self-renewal, proliferation, survival and multipotency
ALDH has been shown to be a functional marker of stem cells in multiple tissues and tumors of multiple organs [8,9,10,11]
Summary
Stem cell antigen-1-positive (Sca-1+) cells from adult mouse hearts were shown to demonstrate increased proliferation and stemness along with potential to differentiate into multiple cardiac cell lineages [1,2,3]. Smits et al have successfully isolated Sca-1+ cells from adult human heart and further demonstrated their ability to differentiate into cardiomyocytes [4]. These studies unequivocally suggest that Sca-1+ cells isolated from cardiac tissue are a subset of cardiac progenitor cells. Circulating progenitor cells, umbilical cord blood cells (UCBCs), hematopoietic stem cells (HSCs), and tissue-specific stem/progenitor cells are being identified based on aldehyde dehydrogenase (ALDH) activity [6,7,8,9,10,11,12]. Instead of solely relying on presence of cell surface markers, which may sometimes vary upon experimental processing during cell isolation, the functional cytosolic ALDH (ALDH1) activity assay is becoming more reliable and widely
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