Complexity of Tracking the Fate of Adult Progenitor Cells.

Abstract

Biological systems are composed of interdependent structures that act in concert to achieve a large range of responses, which could not be produced by a single unit operating alone. Systems comprise subsystems of progressively smaller size, in which the number of components is gradually reduced until individual elements are considered. The partition of living organisms in organs, parenchymal and interstitial compartments, multicellular clusters, and, lastly, single cells yields the possibility of discriminating phenotypic, molecular, and functional heterogeneity at the interunit level. Recent technological advances with increasing resolution for minute details permit to capture and unmask outliers present in large cell populations. Intercellular heterogeneity cannot be ignored; single cell–based approaches are required for the study of stem cells and the tracking of their progeny. The biology of hematopoietic stem cells (HSCs) has clarified the information that can be obtained with population-based and individual cell–based methodologies. The relevance of single cell–derived clonal assays for the understanding of the behavior of HSCs was established at the time of their discovery. This early work has set the stage for future research aiming at the recognition of stem cell fate in solid and nonsolid organs, including the heart. It is unfortunate, however, that the simple concept of cardiac stem cells (CSCs) as individual functional entities is ignored, and the pitfalls of population-based studies in small animal models are dismissed often. It is lamentable that these murine studies have been more broadly interpreted to raise notes of caution about the direction of clinical research.1–5 The antagonistic position of developmental and molecular biologists is founded on the unconditional trust in negative findings collected in inducible lineage-tracing mice in which the irreversible tagging of the targeted cells is used to define their destiny. In most cases, the labeling system involves Cre-mediated excision of a stop …