UV light damages macromolecules, such as DNA [1] and proteins [2], leading to a range of cellular phenotypes, including oxidative stress [3], premature senescence [4], and cell death [5]. The UV spectrum is divided into UV-A (320–400 nm), UV-B (280–320 nm), and UV-C (100–280 nm) regions. The level and type of cellular damage depend on the absorbed dose and wavelength, with shorter wavelengths being more energetically potent and thus more harmful. While UV-B is present in the natural sunlight and poses a risk to skin, UV-C is absorbed by the ozone layer and thus typically not encountered on the Earth's surface. However, their combined use can model conditions of severe DNA damage and extreme oxidative stress or mimic exposure in industrial, laboratory, or medical settings.

Most of the current knowledge on the cellular effects of UV light was derived from experiments on homogenous cell cultures, where all cells were equally exposed to the stressor. However, UV exposure in tissues generates heterogeneous cellular damage, resulting in the coexistence of severely damaged, mildly damaged, and intact cells. Moreover, a large body of evidence shows that even in tissue culture and much more in physiological conditions, within tissues, same-type cells often display heterogeneous phenotypic and genetic features [6]. This might be due to multiple causes, such as uneven exposure to extracellular damaging agents, differences in cell cycle point at the time of stress, or the stochastic nature of somatic mutations that result in somatic mosaicism. Dramatic cell heterogeneity is observed in malignant tissues where genomic instability leads to significant genetic diversification among cells descending from individual cells [7]. Of note, cell heterogeneity increases with aging, especially on the transcriptome level [8], [9], [10], due to epigenetic alterations. The emergence of senescent cells, each affecting the phenotype of surrounding healthy cells, further contributes to age-related heterogeneity of cellular populations.

In such heterogeneous populations the phenotypes of individual cells can be modulated in a non-cell autonomous manner, depending on the features of the cellular community [11]. One example of such non-cell autonomous regulation of cellular phenotypes is the cellular parabiosis, where the presence of healthy cells leads to suppression of aberrant phenotypes in damaged cells [12]. In a reverse scenario, cell competition leads to active removal from tissues of the cells with compromised fitness by their fitter neighbors [13]. Finally, in the bystander effect, intact cells acquire features of the neighboring irradiated cells [14]. Non-cell autonomous factors mediating these interactions could be transmitted through signaling mediated by intercellular ligand-receptor pairing or via various means of intercellular cargo transfer. Direct transfer of cellular contents between adjacent cells is achieved by means of gap junctions, which transfer small molecules - metabolites and ions - or tunneling nanotubes (TNTs), which can transfer proteins and entire organelles. Finally, soluble cargo, such as certain secreted ligands, and extracellular vesicles emanating from cells can be shipped to more remote destinations via the extracellular environment.

Here, we focus on a fundamental aspect of UV biology: whether direct contact with intact neighbors modulates the fate of cells damaged by combined UV-B and C light (hereafter UV light) in a heterogeneous cell culture condition, independent of tissue-specific architecture. Specifically, we analyzed the impact of intact cells on cell death, apoptotic nuclear phenotype, and cellular transcriptome. Finally, we analyzed the communication tools that may be responsible for the transmission of non-cell autonomous factors. We found that the intact cells promote an apoptotic phenotype and reduce transcriptomic response to UV light. This effect of the intact cells was contact-dependent, but it did not rely on GJ and TNTs. However, co-cultures were characterized by dramatically altered ligand-receptor pairing between the two cellular subpopulations.