Tissue resilience: lessons from social resilience

Abstract

Molecular biology could find inspiration from social sciences and ecology research on how communities remain resilient in times of crisis to better understand tissue homeostasis and resilience.

In 2021, at the time of writing this article, societies around the world face the complex challenges and uncertainties of the COVID‐19 pandemic. While the scientific community has worked hard to develop treatments and vaccines against the viral disease, countries are still struggling to cope with the medical, economic, and social impacts of a global health crisis. An important factor in their struggle is the concept of “resilience”, the ability of individuals, organizations, communities, and even whole nations to handle with a major crisis. Obviously, some countries have fared better during the pandemic so far, which owes, in good part, to public and health structures that provide them with said resilience so as to minimize the disturbance caused by COVID‐19. Yet, the concept of resilience could be extended further down from nations or ecosystems to individual organisms and their organs or tissues.

… the concept of resilience could be extended further down from nations or ecosystems to individual organisms and their organs or tissues.

Social scientists have been exploring community resilience (CR)—a community’s ability to cope with a crisis and a core element of emergency preparedness and response—and identified important factors that increase resilience. In biology, the concept of resilience is based on a tissue as the basic individual unit, often without reference to the larger context. In this manuscript, we compare the factors for social resilience to biological functions that are relevant to tissue homeostasis. Based on similarities between each, we suggest that paradigms found to be associated with higher resilience in social communities are also associated with tissue resilience.

Resilience as a research field

Resilience is a concept that originated in the natural sciences to describe the ability of a material to return to homeostasis after disturbance (Norris et al, ²⁰⁰⁸). The Canadian ecologist Holling (1973) applied it to the ecological disciplines to explain the capacity of ecological systems to deal with drastic changes. Since, the concept of resilience has permeated into many disciplines and applications from psychology to disaster risk reduction and from infrastructure resilience in engineering to mental health (Cutter et al, ²⁰⁰⁸; Norris et al, ²⁰⁰⁸). Irrespective of the context, all define resilience as a factor that shortens the effect of a crisis and reduces its negative impact. Significantly, resilience relies on internal resources and is not exclusively affected by the forces that cause the impact (Cutter et al, ²⁰⁰⁸). Thus, CR has become a core element in the field of emergency preparedness and response with a strong focus on the functional continuity of the community and its capacity to cope with changes in times of crisis (Magis, 2010). Social studies revealed that redundancy of resources is crucial for CR (Norris et al, ²⁰⁰⁸), as it provides alternatives when traditional resources cannot be used. Studies have also highlighted the importance of critical infrastructure (CI)—fundamental resources such as electricity, water, and health services—the failure of which can greatly exacerbate negative impacts.

… the concept of resilience has permeated into many disciplines and applications from psychology to disaster‐risk reduction and from infrastructure resilience in engineering, to mental health.

From 2010 to 2014, a group of multidisciplinary experts developed and validated CCRAM (Conjoint Community Assessment Measurement), a tool for assessing community resilience and identified five crucial factors for building CR: leadership, collective efficacy, preparedness, place attachment, and social trust (Leykin et al, ²⁰¹³).

Leadership is the ability to lead a community during an emergency, manage resources, and provide services and relevant information with fairness and transparency. Collective efficacy means mutual support and assistance among members, as well as getting involved in the community’s efforts. Preparedness indicates awareness, clearly defined tasks, and being familiar with emergency regulations. Place attachment is the emotional attachment to and identification with the place of residence. Finally, social trust relates to confidence in and the quality of the relationship between members of the community.

Studies using the CCRAM tool revealed unexpected correlations between these factors and the resilience of a community. For instance, older adults were found to have a higher resilience than younger adults when undergoing traumatic stress, indicating that older adults may be a valuable resource in times of crisis (Cohen et al, ^2016a). Another study explored specific factors associated with vulnerable versus resilient community members and found that collective efficacy was the most significant one. Equally, leadership was an important factor for protecting vulnerable populations but did not play a significant role in resilient populations (Cohen et al, ^2016b). These findings have great value for drafting evidence‐based intervention plans for crisis situations and to strengthen vulnerable sub‐groups in a community.

Resilience in the context of biological tissues

The organs and tissues in multicellular organisms have different physiological roles and often different locations and distinctive boundaries; nonetheless, there are common factors that also relate to social communities. Each tissue consists of individual cells defined by their specific roles. Since tissue homeostasis must be maintained throughout the organism’s lifespan—many decades in some cases—it requires tight regulation and interactions between cells to keep the overall tissue functioning. The cells, in turn, must continuously respond to a variety of complex external and internal signals. Throughout the organism’s lifespan, tissues need to deal with a wide range of changes: acute and chronic inflammatory, metabolic changes, different developmental stages, and various types of insults from DNA damage to extensive injuries just to name a few.

Capitalizing on the extraordinary ability of the “community” of cells to continuously cope with and adapt to changes, sometimes dramatic ones, we herein propose to apply the concept of community resilience to biological tissues. We will describe the factors that enable tissues to adapt and to preserve homeostasis and relate their characteristics to the five main factors of CR: leadership, collective efficacy, preparedness, place attachment, and social trust. This could have indeed wider implications for research and applications in medicine. In cancer research, for instance, a growing body of work suggests that tumors have a lower chance of developing if the overall “cell fitness”, that is, community resilience, remains high. For many years, the major cause for cancer progression was attributed to the accumulation of mutations, but most patients actually amass significant amounts of DNA damage decades before they are diagnosed with cancer. This delay between mutation and tumorigenesis is explained by properties that prevent mutation‐harboring cells from becoming malignant (Marusyk & DeGregori, 2008; Higa & DeGregori, ²⁰¹⁹) and could be a result of overall resilience.

Analogies with human communities

Leadership is frequently described as the ability to react quickly and efficiently during a crisis to restore order. In most tissues, stem cells and progenitor cells could be considered as the analogue of leaders given their crucial role in maintaining homeostasis. To balance the replacement of damaged and aged cells with the need to reduce cancer risk, the proliferation of stem cells and progenitor cells must be closely coordinated. To that end, stem cells monitor and process local and systemic molecular cues; in fact, understanding these signaling mechanisms can help elucidate the molecular etiology of tissue dysfunction, including age‐related degeneration and cancer. The proliferative behavior of different populations of stem cells and progenitor cells displays a remarkable diversity from “high‐turnover” tissues to intense but brief proliferation induced by injury to alternating quiescent and proliferative periods. The small number of stem cells in a tissue thereby fulfills the role of leaders as they can initiate much larger macroscopic processes, such as wound healing, to restore homeostasis.

Collective efficacy crucially depends on communication among cells to initiate acute or chronic responses to changes. Cells use a broad repertoire of signaling mechanisms, and their collective efficacy inside a tissue is manifested in the multitude of chemical and physical interactions. The liver, for instance, consists of mostly hepatocytes—representing about 70% of the cells in the organ—along with other cell types such as intrahepatic cholangiocytes, Kupffer cells, hepatic progenitor cells (HPCs) and hepatic stellate cells (HSCs). According to the needs of the tissue, and in response to changes, the hepatic cells initiate an orchestrated tissue response based on cell‐to‐cell communication to coordinate their actions.

The small number of stem cells in a tissue thereby fulfill the role of leaders as they can initiate much larger macroscopic processes, such as wound healing, to restore homeostasis.

As mentioned above, the longevity of tissues is tightly related to the constant commitment to and investment in being prepared for emergencies. On a cellular level, a considerable amount of energy goes into DNA repair mechanisms to maintain the integrity of the genome. The number of DNA insults in an average cell can be as high as several dozens of thousands per day, which keeps more than a hundred molecular effectors busy in monitoring and responding to damage or stress (Hoeijmakers, 2009). On a higher level, all tissues are patrolled by cells of the immune system specialized in recognizing certain types of stress—pathogens, tissue damage, or malignant cells—that initiate a correct immune response, but that also participate in tissue remodeling and wound healing. Together, these cellular, immune, and other factors constitute the necessary emergency responder that allow tissues to quickly and efficiently handle stress and insults.

In recent years, it has become increasingly clear that place attachment—namely the location and orientation of cells as well as molecular interactions within the tissue—dictates many factors such as turnover rate, phenotype, differentiation status, function, and regulatory mechanisms. For instance, macrophages are extremely plastic cells that can rapidly convert between different functional phenotypes: evacuation of apoptotic bodies, fighting pathogens, or nourishing a healing tissue. Moreover, we can further distinguish different tissue‐resident macrophages, such as osteoclasts in the bone tissue, alveolar macrophages in the lung, Kupffer cells in the liver, and microglia in the brain. Although these share the same precursor, each has a different function that depends on the tissue in which it resides and specifically designed benefits its tissue community. By way of example, resident macrophages in relatively isolated tissues, such as the brain or testes, are associated mainly with tissue remodeling, and their brethren in the colon or the spleen also initiate humoral responses or deal with immune suppression for apoptotic cells. Thus, we can hypothesize that place attachment for specific cell types is a fundamental aspect of tissue resilience and homeostasis.

… we can hypothesize that place attachment for specific cell types is a fundamental aspect of tissue resilience and homeostasis.

The final characteristic of CR is social trust, which cannot be attributed to cells as it requires consciousness. However, we may relate trust to the highly cooperative function of cells inside tissues to maintain and restore homeostasis. Cell‐to‐cell communication is key to ensure that each cell makes the most efficient and beneficial decision vis‐à‐vis the needs of the entire tissue. Even more, the tissue function depends fundamentally on coordination, so that all cells act in harmony. Apoptosis, cell arrest, and senescence are common examples of cells that limit their activity or even terminate their existence for the greater good.

Furthermore, cells inside a tissue rely on predetermined behaviors in response to specific signals. By way of example, endothelial cells show two major responses when the tissue is exposed to hypoxia, such that the selection of the appropriate response depends on the degree and duration of the oxygen deficiency (Bartoszewski et al, ²⁰¹⁹). In acute hypoxia, cells rapidly release inflammatory mediators that, in turn, summon neutrophils to contain the new condition. Chronic hypoxia initiates a signaling cascade and the release of cytokines and growth factors that affects not only the endothelial cells, but also the smooth muscle cells which increases vasoconstriction and proliferation to remodel the vascular wall. This example highlights how the harmony and coordination among various cell populations increases tissue resilience and enables it to react to different perturbations.

Resilience in the cancerous tissue

While normal tissues develop under meticulously controlled conditions from embryonic stage to adulthood, cancerous tissues undergo unrestrained de novo development, caused either by a germline mutation or by the accumulation of somatic mutations (Hanahan & Weinberg, 2011). Unlike normal tissues, all tumor cells are clones of the same progenitor which acquire novel oncogenic properties over time but are still based on the properties of preceding clones. Cancer is therefore a good example of CR in biology: In order to progress and defeat the host defenses, cancer cells must acquire CR characteristics to evade the body’s defense mechanism and recruit a supportive tumor microenvironment that comprises extracellular matrix, stromal cells, immune cells, and blood and lymphatic vascular networks.

A final‐stage metastatic tumor is therefore the result of years of building CR inside the malignant tissue.

A final‐stage metastatic tumor is therefore the result of years of building CR inside the malignant tissue. Cancer clones must overcome the intrinsic and highly efficient DNA damage‐repair mechanisms, tumoricidal immune cells—NK cells, cytotoxic T cells, and M1 macrophages—a lack of blood supply and supportive matrix infrastructure, and hostile conditions in the blood stream or lymphatic system. This “uphill battle” of cancer cells is being fought on a cell‐autonomous and a non‐cell‐autonomous front. On the first front, the genetically damaged cancer cells lose their normal functions or gain oncogenic functions, providing them with proliferative, motile, and invasive capabilities while suppressing their natural tendency to undergo apoptosis (Hanahan & Weinberg, 2011).

The non‐cell‐autonomous front involves cellular interactions inside the cancerous tissue that are cardinal for cancer progression and, eventually, for metastasis. Cancer cells “highjack” numerous physiological processes to manipulate and subordinate the microenvironment for their purpose (Hanahan & Weinberg, 2011). By secreting extracellular vesicles and cytokines, cancer cells can recruit fibroblasts and reprogram them into cancer‐associated fibroblasts, which deposit permissive extracellular matrices that make it easier for cancer cells to crawl out and invade. Cancer cells also convert resident macrophages into tumor‐associated macrophages, which create an immunosuppressive environment (Cooks et al, ²⁰¹⁸). Moreover, cancer cells exploit the endothelial network for angiogenesis. We can therefore assume that the more the tumor makes use of tissue “traits” such as leadership, collective efficacy, preparedness, place attachment, and social trust, the further its resilience will increase and thereby its chances to progress and take over the host’s physiology.

Discussion

Tissues and cancer cells do not have an “agenda”. They survive, develop, and fulfill certain tasks for the greater good, that is, the function of the tissue or organ. Yet, we can also view them in a different perspective, drawing on the CR paradigm. This includes the current view of tissue as a supportive microenvironment, the notions of redundancy and communications, and the capacity of tissues to cope with extreme changes. Alternatively, reviewing the structure of the malignant process reveals comparable strategies that could also be characterized by social processes, such as organized crime in general society (Abadinsky, 2012); current studies perceive CR as a strategy to reduce the impact of organized crime.

We thus suggest that paradigms from social science—for example, community factors associated with higher resilience—could inspire or guide the study of analogous factors in biological tissues. In turn, this can improve our understanding of intra‐tissue processes and predict their dynamics in the face of change (Fig 1). Future research could use the CCRAM tool for the assessment of tissue resilience. Although conjoint analysis is not directly applicable to biological systems, many of the self‐assessment criteria defined by CCRAM can be translated to intra‐ and inter‐cellular properties as perceived by system biologists. For example, a 5‐point Likert scale question “The residents are greatly involved in the community' activities” may be reformulated to address inter‐cellular communication during stress conditions as an analogue for the individual's awareness of its community's wellbeing.

Figure 1. The ability to build long‐lasting tissue resilience depends on the connections between cells as members of a community. Factors such as leadership, collective efficacy, social trust, preparedness, and place attachment are the pillars on which resilience is being cultivated and maintained to preserve tissue homeostasis in the face of changes.

 

Further studies of chemical and mechanical inter‐cellular communication and the extracellular matrices may utilize computational CR models to improve tissue resilience. Consider the post‐hazard CR optimization scheme (Nozhati et al, ²⁰¹⁹), which could be augmented with additional concepts such as local infrastructure and points of interest to devise a set of supportive and corrective actions that need to be taken to increase tissue resilience. Furthermore, since algorithms were already suggested in the literature to solve CR problems, future research may introduce similar concepts into the domain of tissue resilience.

We thus suggest that paradigms from social science – for example, community factors associated with higher resilience – could inspire or guide the study of analogous factors in biological tissues.

In addition, the proposed ontology mapping can generate additional hypotheses for future biological validation. For example, consider the conclusion that elderly members in a community can become a stabilizing element contributing to efforts to restore order. Can we hypothesize that aging and senescent cells, typically perceived as fragile elements, could be a resource in a time of crisis and could contribute to tissue resilience? Indeed, cellular senescence has been reported to play a major role in wound healing and immune suppression. This suggests that even if cell fitness declines for aging cells, the tissue can still profit from their unique properties. From another perspective, the different factors that were found to be significant in resilient and vulnerable sub‐communities could be implemented to activate different elements in a time of a crisis, according to the exposed tissue’s status.

Another suggestion refers to the routine/emergency ratio. In the social context, resilience is a means to bridge the gap between these periods (Norris et al, ²⁰⁰⁸; Magis, ²⁰¹⁰). Prompting resilience and enhancing the CR factors during routine enriches community life and promotes its capacity to cope with emergencies. Similarly, we could explore means to improve tissue resilience during times of relative homeostasis, to maximize the potential response to acute crisis. In the case of cancer, where CR translates to prosperous tumors, CR factors can be targeted to decrease the ability to promote the malignant process. While many targeting strategies have been described to manipulate and modify specific functions in tissues, viewing the tissue as a community assembled by a web of connections between its cellular members has potential to help us gain novel insights into cell biology. Proper use of models based on leadership, collective efficacy, preparedness, place attachment, and social trust could be instrumental in identifying strengths and weaknesses.

Conflict of interest

The authors declare that they have no conflict of interest.

EMBO reports (2021) 22: e52926.