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

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.