Clonal and systemic analysis of long-term hematopoiesis in the mouse.

TLDR

The study proposes a model in which lineage‑restricted differentiation and clonal flux arise from mechanisms acting on an expanding pool of totipotent cells rather than from distinct stem‑cell classes. The authors tracked the temporal in‑vivo fate of 142 individual stem‑cell clones in 63 reconstituted mice, using this data to support the proposed model. Sequential analyses of peripheral‑blood lineages revealed that developmental behavior is largely time‑dependent, with early post‑engraftment fluctuations that stabilize into a system dominated by a few totipotent clones, showing that single stem‑cell clones can sustain lifelong hematopoiesis and that mono‑ or oligoclonality may be a hallmark of long‑term reconstituted systems.

Abstract

We have analyzed the temporal in vivo fate of 142 individual stem cell clones in 63 reconstituted mice. Long-term sequential analyses of the four major peripheral blood lineages, obtained from animals engrafted with genetically marked stem cells, indicate that developmental behavior is primarily a function of time. As such, the first 4-6 months post-engraftment is characterized by frequent fluctuations in stem cell proliferation and differentiation behavior. Gradually, a stable hematopoietic system emerges, dominated by a small number of totipotent clones. We demonstrate that single stem cell clones are sufficient to maintain hematopoiesis over the lifetime of an animal and suggest that mono- or oligoclonality may be a hallmark of long-term reconstituted systems. A model is proposed, wherein lineage-restricted differentiation and dramatic clonal flux are consequences of mechanisms acting on an expanding pool of totipotent cells and are not indicative of intrinsically distinct stem cell classes.