Partial Reprogramming Uncouples Cellular Identity from Cellular Aging in Mesenchymal Stromal Cells

The epigenetic landscape proposed by Waddington has long provided a conceptual framework for cellular differentiation [1]. In this model, pluripotent cells positioned at the summit of a developmental landscape progressively descend toward terminally differentiated states. The discovery of induced pluripotent stem (iPS) cells demonstrated that differentiated somatic cells can be reprogrammed back to pluripotency, revising the concept of irreversibility [2]. Emerging evidence suggests that rejuvenation does not necessarily require a return to this summit. Rather, partial reprogramming(definition) may restore youthful cellular properties while preserving lineage identity [3–5]. Here, I propose a conceptual framework in which rejuvenation occurs along the slope of the Waddington landscape. In this view, cellular identity and cellular aging represent partially separable dimensions of cell state. In mesenchymal stromal cells (MSCs), chemical, mechanical, and transient gene-expression strategies converge on restoration of youthful function without complete dedifferentiation [7–12]. This perspective suggests that partial reprogramming may enable the generation of transcriptionally diverse MSC populations, providing a conceptual basis for precision regenerative medicine.