Regenerative-system dysfunction in organ fibrosis: Maladaptive regeneration, fibrotic memory, and therapeutic reprogramming

Table 1 Mechanisms contributing to regenerative-system dysfunction in organ fibrosis

Module	Relevant compartment	Organ/model and direct evidence	Scoped evidence grade	Therapeutic implication and limit
Exhaustion and senescence	ATII cells; differentiated renal epithelia; hepatic stellate cells	Mouse ATII perturbation with human IPF observations; renal G2/M perturbation and post-obstructive senolytic treatment[17,19,20]. Stellate-cell senescence can limit liver fibrosis[22]	Strong for specified epithelial mechanisms; exhaustion is not established by senescence markers alone. Direction differs by cell type	Target harmful states selectively. Depletion is not rejuvenation; a pilot trial does not establish fibrosis reversal
Persistent maladaptive repair states	Transitional alveolar cells; proximal tubular cells; hepatic ductular/progenitor-associated cells	Lung transitional-state perturbation; renal stress perturbation; mouse ductular-reaction/Hedgehog experiments[26,27,47]	Strong in selected lung models; moderate, model-specific renal/liver causal support. Human state maps remain associative	Test maturation and functional recovery separately from disappearance of a marker
ECM/mechanotransduction	Fibroblasts; ATII cells; extracellular niche	Cultured lung fibroblast stiffness-switch assay; YAP/TAZ perturbation; murine alveolar tension model; human decellularized lung ECM conditioning[13,32-34]	Direct culture memory; strong selected mechanistic effects. Human in vivo memory and whole-organ restoration are unproven	Normalize harmful cues without assuming all ECM is detrimental or that mechanics alone restores tissue
Inflammatory conditioning	Macrophages and immune-epithelial niches	Conditioned macrophage/rechallenge-transfer experiments in HClO-induced mouse fibrosis; postviral lung niche perturbation[39,42]	Moderate, direct within named models; conditioning effects vary by endpoint. Macrophage NASH epigenomics is not a withdrawal test[43]	Distinguish harmful training, protective tolerance, and continuing niche stimulation
Metabolic/mitochondrial dysfunction	Alveolar and renal epithelia	Mouse/human-associated CD38 epithelial-aging work and renal ferroptotic-stress perturbation[21,47]	Moderate, organ-specific mechanistic support; metabolic-memory erasure remains emerging/unproven	Measure cell fitness and fibrosis separately from durable post-withdrawal state correction
Epigenetic stabilization	Systemic-sclerosis dermal fibroblasts; liver macrophages as a contrasting context	TGFB2 enhancer persistence/perturbation in patient-derived fibroblasts; macrophage chromatin remodeling during ongoing steatohepatitis[14,43]	Strong for the specified enhancer mechanism ex vivo; macrophage memory remains inferred. No generalized progenitor-memory grade	Test durable locus- and cell-specific correction; avoid equating altered chromatin with erased memory
Cross-organ state convergence	Distinct epithelial, immune, and stromal populations	Lung, human liver, and kidney state/niche analyses; functional experiments apply only to the modules actually tested[8,10,36,37]	Moderate for recurrent associations; emerging for a universal causal sequence	Use shared signatures for target nomination, followed by organ-specific perturbation

Grades apply to the named mechanism, model, cell type, and endpoint, not to an entire organ or therapeutic class. Directness, memory, reversibility, and clinical efficacy are separate judgments (“Review methodology and evidence appraisal”). ATII: Alveolar type II; IPF: Idiopathic pulmonary fibrosis; YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; ECM: Extracellular matrix; HClO: Hypochlorous acid; NASH: Nonalcoholic steatohepatitis.

Table 2 Operational assessment of proposed fibrotic-memory layers

Layer/carrier	Organ/model and test actually performed	Directness and scoped grade	Reversibility and remaining test
Epigenetic/dermal fibroblasts	Systemic-sclerosis fibroblasts: Retained TGFB2 enhancer program and chromatin-directed perturbation[14]	Direct ex vivo; strong for this enhancer mechanism, not for all chromatin signatures	Molecular program is perturbable in the assay; durable human tissue reversal is not established
Mechanical/fibroblasts	Cultured lung myofibroblasts transferred from stiff to soft substrates[13]	Direct culture persistence; moderate for generalization beyond the model	Retention depends on exposure history and assay conditions. Clinical memory erasure is untested
Inflammatory/macrophages	Conditioning, subsequent challenge, and transfer in an HClO-induced mouse fibrosis model[39]	Direct, model-specific response modulation; moderate. BCG and low-dose LPS have different effects	Fibrosis-modifying responses are demonstrated; durable normalization of human immune states is not
Niche/ECM	Human decellularized IPF matrix conditions cultured fibroblasts; postviral mouse lung immune-epithelial niche is functionally perturbed[34,42]	Direct niche instruction/persistence in these settings; moderate. Continued niche exposure is not cell-autonomous memory	Require removal of residual stimuli, cross-transfer controls, and durable functional follow-up to establish autonomous retention
Metabolic/epithelial cells	Renal metabolic-state and ferroptotic-stress studies demonstrate injury-associated dysfunction, not the full withdrawal-retention-reversal sequence[46,47]	Inferred; emerging for metabolic memory	Direct metabolic-memory erasure is unproven; test after stress and treatment withdrawal
Epithelial state/renal or alveolar cells	Senescent renal epithelia persist after relief of obstruction; senolytic treatment improves fibrosis without epithelial-specific targeting[20]. KRT8-associated lung states are a distinct context[8,25]	Direct, moderate evidence for the post-obstructive senescent-state example; KRT8 cell-autonomous memory remains inferred	Depletion is not reprogramming of surviving cells. Durable maturation and organ recovery require separate demonstration
Stromal activation state/hepatic stellate cells	Lineage-traced stellate cells deactivate after experimental liver-injury withdrawal but retain enhanced reactivation potential[52]	Direct, moderate evidence for sensitized activation-state memory; its epigenetic mechanism is not established by this experiment alone	Partial deactivation is demonstrated; complete return to a naive state or durable therapeutic memory erasure is not

Operational criteria: Document antecedent exposure, a suitable resolution/rest interval, and separation from continuing injury. Direct support comes from withdrawal-associated persistence, altered re-exposure responses, or selective perturbation of an already retained state. Perturbation only during ongoing injury is not a memory test. Molecular correction, cell depletion, histological regression, and functional recovery are different outcomes. TGFB2: Transforming growth factor beta 2; HClO: Hypochlorous acid; BCG: Bacillus Calmette-Guérin; LPS: Lipopolysaccharide; ECM: Extracellular matrix; IPF: Idiopathic pulmonary fibrosis; KRT8: Keratin 8.

Table 3 Organ-specific repair compartments, mechanistic evidence, memory, and reversibility

Organ/context and compartment	Mechanism: Model and evidence grade	Memory: Directness and boundary	Reversibility/translational limit
Lung/IPF and postviral injury. ATII and airway progenitors; fibroblasts and immune niche are separate	Strong in selected mouse ATII-senescence, transitional-state, and mechanical-tension experiments; human observations support relevance[17,27,33]	Direct cultured fibroblast mechanical retention[13]. Postviral niche persistence is distinct from cell-autonomous epithelial memory[42]	Preclinical effects are context-specific; the open-label senolytic pilot establishes feasibility, not antifibrotic efficacy[23]
Kidney/AKI-CKD. Differentiated proximal tubular epithelia	Direct G2/M and ferroptotic-stress perturbation in mouse injury models; strong/moderate within those mechanisms. Human failed-repair signatures are associative[9,19,47]	Direct, moderate post-obstructive persistence and senolytic-response evidence, not epithelial-specific ablation[20]; not every failed-repair signature meets memory criteria	Partial experimental benefit does not establish full renal reconstruction or reprogramming of surviving cells
Liver/steatohepatitis, cirrhosis, and experimental regression. Hepatocytes, ductular/progenitor-associated cells, macrophages, stellate cells	Moderate direct ductular/Hedgehog mechanism in mouse models; human cirrhotic niche interactions add distinct evidence[10,26]	Macrophage epigenetic adaptation during ongoing disease is inferred memory[43]. Direct sensitized stellate-cell reactivation follows experimental regression[52]	Partial stromal inactivation differs from memory erasure. Arid1a deletion supports murine fibrosis reduction/regression, not human efficacy[63]
Intestine/fibrostricturing Crohn’s disease. Crypt stem cells and fibroblasts are distinct	Moderate direct cadherin-11 fibroblast evidence from patient-derived cells and experimental colitis fibrosis[56]	Emerging/unproven for stem-cell memory or an autonomous epithelial cause of fibrostenosis	Stromal pathway modification is not demonstrated restoration of crypt function or established stricture reversal
Heart/early injury vs established scar. Cardiomyocytes and resident fibroblast lineages	Strong direct lineage/ablation evidence for periostin-positive myofibroblast contribution to mouse scar and necessary acute healing[57]	Post-injury deactivation is observed; retained pathogenic responsiveness and therapeutic memory erasure are not established by that observation alone[57]	Experimental cardiac lineage conversion[58] and negative chronic-scar cell therapy[7] address different stages; neither establishes human scar reversal
Skin/experimental scarring and systemic sclerosis. Dermal fibroblast and adiponectin-marked lineages	Strong lineage/functional support for selected dermal populations; lineage origin alone does not establish every population’s necessity[59,60]	Direct ex vivo TGFB2 enhancer-memory evidence in systemic-sclerosis fibroblasts[14]; not all progenitors	Enhancer perturbability and lineage plasticity do not establish complete or safe human tissue reversal
Bone marrow/myelofibrosis models. Hematopoietic progenitors interact with distinct stromal populations	Strong Gli1 lineage/ablation evidence in ThPO/JAK2-associated models; LepR/PDGFRα evidence in a separate marrow model; supportive human findings[11,61]	Emerging/inferred memory: These studies do not perform a definitive retained-state withdrawal/rechallenge test	Preclinical stromal targeting does not establish durable human memory erasure; Gli1 and LepR labels are not assumed equivalent

Evidence is specific to the named cell, organ, model, and endpoint; no overall cross-organ confidence score is assigned. IPF: Idiopathic pulmonary fibrosis; ATII: Alveolar type II; AKI-CKD: Acute kidney injury-chronic kidney disease; TGFB2: Transforming growth factor beta 2; ThPO: Thrombopoietin; LepR: Leptin receptor; PDGFRα: Platelet-derived growth factor receptor α.

Table 4 Classification and evidence status of therapeutic strategies

Approach/category	Organ, model, and target	Directly supported effect/evidence stage	What is not established/main limitation
Progenitor-state rejuvenation/reprogramming only if durable and controlled	Partial-reprogramming experiments in aging/progeroid mice and tissue-repair settings[53]	Preclinical improvement in selected age-associated cellular and tissue phenotypes	Not a general fibrosis trial, a validated memory-erasure assay, or established human progenitor rejuvenation
Epigenetic state correction/candidate direct reprogramming	Systemic-sclerosis dermal fibroblast enhancer perturbation[14]; Arid1a deletion in murine liver-fibrosis/regression models[63]	Direct locus-level mechanism ex vivo; preclinical liver-fibrosis reduction, including intervention after injury cessation	No established human antifibrotic efficacy or complete memory erasure; delivery, identity stability, and oncogenic risk require separate testing
Direct lineage conversion/reprogramming	Murine cardiac fibroblasts converted toward induced cardiomyocytes after injury[58]	Animal proof of lineage conversion and selected functional effects	Not reversal of established chronic human scar; efficiency, maturation, integration, and lineage control remain limiting
Senomorphics/state modulation; senolytics/cell depletion	Mouse pulmonary fibrosis, post-obstructive renal senescence, and an open-label human IPF pilot[15,20,23]	Preclinical benefit in specified endpoints; human pilot feasibility	Senolysis is not reprogramming; pilot data do not establish antifibrotic efficacy. Beneficial senescent states may be lost
ECM/mechanotransduction modulation/niche intervention	Cultured lung fibroblast stiffness-switch and YAP/TAZ perturbation models[13,32]	Direct effects on mechanical retention or activation in the particular assay; primarily preclinical	Matrix instruction is not cell-intrinsic memory; clinical restoration and optimal timing are unproven
Immune-state modulation/complementary unless durable resetting is shown	Macrophage conditioning in mouse systemic-sclerosis-like fibrosis[39]; IL-22 liver progenitor studies[64]	Conditioning changes selected fibrosis outcomes; IL-22 promotes progenitor expansion experimentally, with human associations	Opposing conditioning effects; IL-22 proliferation is not demonstrated fibrosis reversal. Infection and impaired repair require assessment
Metabolic correction/state modulation	CD38-related alveolar aging and renal ferroptotic-stress models[21,47]	Direct preclinical modification of specified stress/repair pathways and fibrosis-associated outcomes	No complete withdrawal-based metabolic-memory erasure; systemic and cell-specific effects need evaluation
Cell replacement/separate regenerative strategy	Tested cell products in chronically scarred rodent hearts[7]	Negative primary evidence: No rejuvenation in that chronic-scar setting	No class-wide efficacy inference; engraftment, maturation, host response, and disease stage must be tested for each product
Organoid-guided screening/research platform, not itself therapy	Human pluripotent-stem-cell-derived nephron organoids and expandable adult liver cultures[50,51]	Direct platform evidence for development/injury modeling and culture-based experimentation	Memory washout/rechallenge protocols are a proposed extension here; no direct patient effect from screening alone. Incomplete niche and model fidelity remain limitations

A mechanistic or model-specific result is not a clinical evidence grade. Reprogramming requires controlled and durable intrinsic state, identity, or trajectory correction. Depletion, transient pathway modulation, matrix correction, cell delivery, and screening are different categories. IPF: Idiopathic pulmonary fibrosis; ECM: Extracellular matrix; YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; IL-22: Interleukin-22.

Table 5 Experimental platforms for distinguishing association, causality, and memory

Platform	Primary contribution/causal inference	Memory or reversibility requirements	Main limitation
Single-cell/single-nucleus RNA sequencing	Identifies cell states and heterogeneity; not causal by itself[8,37]	Longitudinal sampling can suggest persistence; exposure history and a functional test are needed	Sampling bias, dissociation effects, and lack of spatial context
Spatial transcriptomics	Maps tissue architecture and candidate interactions; not causal alone[65,66]	Can localize retained niches, but cannot alone exclude continuing stimulus	Resolution, analytical inference, and tissue-sampling limitations
Multiome/chromatin profiling	Links regulatory and transcriptional states; stronger inference requires perturbation[48]	Test retained programs after withdrawal and selectively perturb the candidate state	A chromatin signature is not itself proof of memory
Lineage tracing/barcoding	Establishes origin and fate, not causal necessity without an additional intervention[28]	Combine with withdrawal/re-exposure and appropriate functional perturbation[52]	Label specificity, recombination efficiency, and mostly experimental-animal use
Inducible perturbation/Perturb-seq	Tests candidate regulatory contributions when controls and endpoints are appropriate[29]	Perturb an already retained state after injury reduction; assess later function and re-exposure	Perturbation during ongoing injury may identify an injury pathway rather than memory
Organoids/expandable epithelial cultures	Experimentally tractable human-derived models[50,51]	Add and validate injury, washout, recovery, and rechallenge; this is a proposed extension, not automatic platform capability	Incomplete immune, vascular, and mechanical niches; variable maturation
Ex vivo diseased ECM/tissue systems	Tests matrix-conditioned behavior and niche instruction[34]	Transfer away from diseased ECM or remove residual stimuli to test cell-autonomous retention	Continued ECM exposure is continuing niche instruction, not proof of intrinsic memory
Longitudinal human sampling	Establishes clinical relevance and candidate biomarker trajectories[9,20]	Document injury reduction, recovery interval, and confounders; couple associations to functional models	Limited repeat sampling and no routine direct genetic causal test

Functional tissue recovery must be measured separately from cell-state or molecular normalization. Platform availability does not guarantee a valid memory test. Direct evidence depends on the exposure, resolution, transfer/rechallenge, and perturbation design described in “Definition and conceptual boundaries”. ECM: Extracellular matrix.

Table 6 Relationship of the proposed framework to selected major reviews

Ref.	Principal scope	Overlap with this review	Additional emphasis of the present framework
Henderson et al[3], 2020	Fibrosis mechanisms and therapeutic development across organs	Immune-stromal interactions, ECM remodeling, and antifibrotic targets	Aligns repair-compartment identity with operational persistence tests and separates mechanism, memory, and clinical benefit
Zhu et al[4], 2021	Maladaptive regeneration and developmental pathways in NASH/fibrosis	Repair can become fibrogenic rather than simply insufficient	Compares seven organs without assuming identical progenitor biology; distinguishes persistent repair from directly tested memory
Distler et al[5], 2019	Shared and organ-specific fibrosis mechanisms	Conserved signaling alongside disease- and organ-specific biology	Uses model- and cell-specific directness to constrain cross-organ grades and therapeutic classification
Netea et al[67], 2020	Trained immunity in health and disease	Durable response changes and epigenetic/metabolic conditioning	Requires fibrosis-relevant endpoints and separates beneficial tolerance, ongoing niche stimulation, and autonomous retained states
Present review	Evidence-calibrated injury-repair-memory synthesis	Integrates established concepts rather than claiming a wholly new mechanism	Proposes testable links, explicit memory boundaries, a reprogramming/modulation/platform distinction, and a staged translational roadmap

This comparison describes differences in emphasis, not absence of related concepts from prior reviews or proof that the present framework is mechanistically superior. ECM: Extracellular matrix; NASH: Nonalcoholic steatohepatitis.