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In addition to providing nutritional support and oxygen supply, activated EC express chemokines and
adhesion molecules, facilitating the recruitment of leukocytes, monocytes, and neutrophils [120,121] . Pericytes, a
class of tissue-resident mesenchymal stem cells, play a critical role in the stabilization of neovessels and
regulating MMP activity [10,99,116] . In both wound repair and cancer, pericytes deviate from the EC and
vascular basement membrane, undergoing a phenotypic transformation that regulates angiogenesis,
inflammation, fibrosis, tissue regeneration, and re-epithelialization [122,123] . All these functional aspects of
pericytes in an emergent wound repair scenario are critical in establishing a pre-metastatic niche, which is
critical for tumor growth and progression .
[124]
STROMAL MEMORY
The concept of cellular "memory" can be defined as when cells maintain an altered phenotypic or functional
state proceeding with an initial environmental stimuli/insult. Myeloid lineage cells like monocytes, NK cells,
macrophages, and neutrophils exhibit innate immune memory, a manifestation of cellular memory [125,126] .
Research over the past two decades has demonstrated that these cells exhibit protective or cross-protective
mechanisms against recurring infections through heightened activation of the innate immune response.
This heightened response is driven by pattern recognition receptors (PRRs) on myeloid cells, allowing
recognition of pathogen-associated molecular patterns (PAMPs). Activation of PRRs by PAMPs triggers the
expression of genes involved in inflammatory and immune responses [127-129] .

Fibroblast memory
Emerging evidence suggests that non-immune cells also possess a memory of past insults such as
inflammation, enabling them to mount rapid responses to emergent situations like injury or infection. The
biological mechanisms regulating cellular memory are multifaceted, involving various processes such as
alterations in chromosomal accessibility due to epigenetic modifications, increase in expression of activation
receptors, and priming of cellular signaling networks [121,130-133] .

Naik et al. were the first to discover that epithelial stem cells exposed to inflammation retain cellular
memory, leading to enhanced repair responses to future tissue-related injuries [121,134] . This phenomenon
extends to fibroblasts, which develop an inflammatory memory upon exposure to exogenous challenges
such as lipopolysaccharide (LPS) or endogenous inflammatory signals like tumor necrosis factor α
[121]
(TNF-α) . For instance, human gingival fibroblasts pretreated with LPS showed no tolerance but
maintained cytokine and chemokine expression after secondary LPS treatment . Similarly, in conditions
[135]
like rheumatoid arthritis, fibroblasts such as synoviocytes exhibit gene-specific priming by altering
chromatin following chronic exposure to inflammatory signals like TNF-α, leading to enhanced and
prolonged chemokines and cytokine production upon subsequent interferon (γ) stimulation [132,136] .
Klein et al. have also observed that LPS primes synovial fibroblasts to sustain inflammatory responses by
[131]
changing the epigenetic configuration at gene promoters regulating LPS-induced cellular responses .

In patients with tendinopathy, stromal fibroblast activation markers such as podoplanin and vascular cell
adhesion molecule (VCAM-1) are notably elevated compared to healthy tendon tissues. This elevation
persists even after the gradual decline in inflammatory gene signatures following the removal of stimuli like
IL-1β, suggesting that activated fibroblast memory maintains a persistent activated state rather than
sustaining inflammatory responses . Additionally, in rheumatoid arthritis, sustained synovial
[130]
inflammation is also attributed to persistent activation of nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-κB) signaling induced by TNF-α, facilitated by upregulation of TNF receptors and
proximal signaling components, and downregulation of negative feedback inhibitors involved in the
homeostatic balance of the NF-κB signaling pathway . Epigenetic modifications are also known to
[136]
regulate epithelial stem cell memory [121,131,132,134] .