Progenitor Cells and Lineage Plasticity in Regeneration

Tissue regeneration is often drawn as a one-way hierarchy: a stem cell produces a progenitor, the progenitor expands, and its descendants mature into one or more specialized cell types. That model describes many uninjured tissues, but injury can change the rules. Cells that normally make only a restricted set of descendants may broaden their output, return to a stem-like state, or adopt a fate used by a neighbouring lineage. These responses are forms of lineage plasticity. [1] [2]

Who This Is Useful For

This page is useful for readers comparing stem cells, progenitor cells, and differentiated cells in regenerative studies. It also provides a framework for interpreting claims that an injury has created a new stem-cell population or caused one cell type to become another, conclusions that require evidence about both cell origin and descendant fate. [2] [9]

Progenitors Are Defined by What They Do

An adult stem cell is generally expected to self-renew over the long term while generating differentiated descendants. A progenitor lies further along a developmental path: it can divide and produce one or several related cell types, but it commonly has less durable self-renewal and a more restricted output. In practice, these labels depend on the assay, observation period, and tissue context rather than on a single universal molecular marker. [1] [9]

The distinction becomes especially important after damage. A cell classified as a short-lived progenitor during ordinary turnover may generate long-lived clones after injury. This does not show that its normal identity was described incorrectly; it can instead reveal a latent capacity that is activated only when the usual stem cells or niche signals are disrupted. [2] [3] [4]

Cell Hierarchy and Plasticity at a Glance

Intestine: Committed Progenitors as a Reserve

During normal intestinal turnover, rapidly cycling Lgr5-positive stem cells supply progenitors for absorptive and secretory lineages. Dll1-high cells are immediate descendants committed toward secretory fates: lineage tracing under uninjured conditions produced small, short-lived clones containing secretory cell types. When those cells were labelled before crypt damage, however, some generated long-lived tracing events characteristic of regenerated intestinal stem cells. [3]

The experiment shows that lineage commitment can be conditional rather than irreversible. It does not show that every intestinal progenitor responds equally, or that the same cells dominate every form of injury. Later work identified rare, damage-induced Clusterin-positive cells that transiently expand and help reconstitute the Lgr5-positive compartment, illustrating that multiple cellular routes can support intestinal recovery depending on the injury model. [3] [10]

Airway and Skin: Damage Changes Permitted Fates

In the mouse airway, selective loss of basal stem cells caused committed luminal secretory cells to proliferate and generate stable basal stem cells. Lineage tracing and functional assays showed that the newly produced basal cells could participate in epithelial repair. Direct contact with surviving basal cells suppressed this response, indicating that plasticity was regulated by the local cellular environment rather than being continuously active. [4]

Mouse skin provides another example. During uninjured maintenance, Gata6-positive sebaceous-duct cells contribute within a restricted territory. After wounding, labelled descendants moved into the interfollicular epidermis, acquired long-term self-renewal, and produced a broader set of epidermal lineages. The wound therefore changed both where the cells could contribute and the range of fates they displayed. [6]

Liver: Plasticity Depends on Which Population Can Respond

The adult liver usually replaces lost hepatocytes through division of surviving hepatocytes rather than through a separate broadly active progenitor pool. In mouse models combining liver injury with impaired hepatocyte proliferation, lineage-labelled cholangiocytes from the bile ducts produced substantial numbers of functional hepatocytes. The study therefore supports a facultative route: biliary cells can supply hepatocytes when the usual source is experimentally constrained. [5]

This context dependence prevents a simple statement that cholangiocytes are the routine source of new hepatocytes. The observed lineage switch depended on particular combinations of injury and blocked hepatocyte proliferation. More generally, the cell population that repairs a tissue can reflect which populations survive, which can still divide, and which niche signals are present. [2] [5]

Plasticity Does Not Erase All Lineage Boundaries

A regenerative cell can look morphologically simple and express progenitor-associated genes without acquiring unlimited potency. In axolotl limb regeneration, grafting and tissue-tracing experiments showed that cells entering the blastema largely retained memory of their tissue of origin. Muscle descendants remained in muscle, Schwann-cell descendants remained neural, and cartilage-derived cells contributed to connective tissues but not muscle. [8]

Regeneration can therefore combine plastic cell states with stable lineage constraints. The relevant question is not simply whether a cell is plastic, but which boundaries it can cross, under which injury conditions, for how long, and whether its descendants restore organized tissue. [2] [8]

The Niche Helps Set the Range of Possible Fates

Injury changes extracellular matrix, mechanical forces, inflammatory signals, and contact with neighbouring cells. These changes can remove signals that stabilize an existing identity or provide signals that support proliferation and a different lineage program. The airway experiment, in which contact with basal cells inhibited secretory-cell reversion, is a direct example of cell identity being constrained by local neighbours. [2] [4]

Plasticity is therefore a property of a cell within an environment, not a fixed score belonging to the cell alone. As repair resolves, injury-associated states may disappear and ordinary lineage behaviour may resume; persistent or misregulated plasticity can instead accompany metaplasia and cancer. [2] [7]

How Lineage Plasticity Is Demonstrated

Genetic lineage tracing marks a defined starting population and passes the label to its descendants. When marking occurs before injury, researchers can ask whether cells from that population later occupy a different compartment or generate fates outside their normal output. Clonal analysis can determine whether multiple cell types arose from one labelled ancestor, while ablation and transplantation or organoid assays can test whether the labelled cells are functionally required or capable of sustained regeneration. [3] [4] [9]

Lineage tracing is not automatically definitive. A promoter may label more cell types than expected, may become active after injury, or may mark only a fraction of the candidate population. Labels can also dilute, and a cell that expresses markers from two lineages may be transitional without completing a functional fate change. Studies are strongest when labelling specificity, timing, cell-state measurements, descendant function, and independent tracing strategies converge. [5] [9]

Ageing Changes Both Progenitors and Their Context

Regenerative capacity commonly declines with age, but this cannot be assigned to progenitor number or plasticity alone. Tissue stem and progenitor cells accumulate intrinsic changes, while their niches also undergo changes in inflammation, metabolism, extracellular matrix, and intercellular signalling. The relative contribution of these processes differs among tissues and cell populations. [7] [11]

Evidence that a young cell population changes fate after a defined injury therefore does not establish that an aged tissue will use the same route with the same efficiency. Ageing may alter cell survival, lineage bias, signal responsiveness, or the ability of a temporary regenerative state to resolve. These variables need to be measured directly rather than inferred from cell markers alone. [9] [11]

Evidence Quality and Interpretation

Confidence is strong that committed progenitors and differentiated cells can display injury-induced lineage plasticity in specific animal tissues. Prospective genetic tracing and functional tests support this conclusion in mouse intestine, airway, skin, and liver. [3] [4] [5] [6]

Confidence is also strong that this plasticity is restricted by lineage and context. Different injuries recruit different sources, and axolotl blastema cells retain substantial tissue-of-origin constraints despite entering a regenerative state. [5] [8] [10]

Confidence is lower when extending these findings to the scale of adult human regeneration. Much of the causal evidence comes from engineered lineage-tracing, ablation, or injury models in mice and other animals. Human tissue measurements and organoids can identify compatible states, but they generally cannot reconstruct a person's complete cellular ancestry with the same experimental control. [1] [2] [9]

What This Does Not Mean

• It does not mean every progenitor is a stem cell; long-term self-renewal and sustained lineage output must be demonstrated. [1] [9]
• It does not mean injury makes adult cells pluripotent; most observed changes remain restricted to particular tissues and lineages. [2] [8]
• It does not mean marker changes prove a lineage switch; cell ancestry and descendant function are separate measurements. [5] [9]
• It does not mean plasticity is always beneficial; regenerative state changes can be incomplete, persistent, or associated with metaplasia and tumorigenesis. [2] [7]
• It does not mean mechanisms demonstrated in animal injury models occur at the same frequency or scale in adult humans. [1] [5]

Practical Interpretation Examples

• If a progenitor produces a wider range of descendants after injury: this supports context-dependent plasticity only if the starting population was labelled before injury and the new fates were functionally established. [3] [9]
• If a cell expresses both old and new lineage markers: it may occupy a transitional state, but co-expression alone does not show completed conversion or long-term self-renewal. [2] [9]
• If plasticity appears only after stem-cell ablation: the result may reveal a genuine reserve mechanism while still saying little about ordinary maintenance or less severe injury. [4] [5]

Related Reading

• Stem Cells in Regeneration
• Cell Dedifferentiation and Regeneration
• Tissue Niches and Regenerative Capacity
• Model Systems in Regeneration Research
• Why Regeneration Declines With Age

Summary

Progenitor cells normally occupy intermediate positions between self-renewing stem cells and mature tissue cells, but injury can expose capabilities that are not visible during routine maintenance. Committed progenitors may regain stem-like activity, broaden their output, or cross a nearby lineage boundary. These responses are real but conditional: tissue origin, surviving cell populations, niche signals, injury type, and age all influence what a cell can contribute. Lineage plasticity is therefore best understood as a measured change in fate under defined conditions, not as unrestricted regenerative potential. [1] [2] [9] [11]

References

1. Wells, J. M., Watt, F. M. "Diverse mechanisms for endogenous regeneration and repair in mammalian organs." Nature (2018). https://www.nature.com/articles/s41586-018-0073-7
2. Merrell, A. J., Stanger, B. Z. "Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style." Nature Reviews Molecular Cell Biology (2016). https://www.nature.com/articles/nrm.2016.24
3. van Es, J. H. et al. "Dll1-positive secretory progenitor cells revert to stem cells upon crypt damage." Nature Cell Biology (2012). https://www.nature.com/articles/ncb2581
4. Tata, P. R. et al. "Dedifferentiation of committed epithelial cells into stem cells in vivo." Nature (2013). https://www.nature.com/articles/nature12777
5. Raven, A. et al. "Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration." Nature (2017). https://www.nature.com/articles/nature23015
6. Donati, G. et al. "Wounding induces dedifferentiation of epidermal Gata6-positive cells and acquisition of stem cell properties." Nature Cell Biology (2017). https://www.nature.com/articles/ncb3532
7. Ge, Y., Fuchs, E. "Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer." Nature Reviews Genetics (2018). https://www.nature.com/articles/nrg.2018.9
8. Kragl, M. et al. "Cells keep a memory of their tissue origin during axolotl limb regeneration." Nature (2009). https://www.nature.com/articles/nature08152
9. Romagnani, P., Rinkevich, Y., Dekel, B. "The use of lineage tracing to study kidney injury and regeneration." Nature Reviews Nephrology (2015). https://www.nature.com/articles/nrneph.2015.67
10. Ayyaz, A. et al. "Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell." Nature (2019). https://www.nature.com/articles/s41586-019-1154-y
11. Brunet, A., Goodell, M. A., Rando, T. A. "Ageing and rejuvenation of tissue stem cells and their niches." Nature Reviews Molecular Cell Biology (2023). https://www.nature.com/articles/s41580-022-00510-w