Targeting Cellular Senescence to Heal Non-Healing Wounds

An accumulation of senescent cells takes place throughout the body with age. Cells become senescent constantly, the vast majority as a consequence of hitting the Hayflick limit on replication of somatic cells. In youth, these cells are efficiently removed, either via programmed cell death, or destroyed by the immune system. In later life, removal processes slow down, while the damaged state of tissue provokes ever more cells into becoming senescent. In older people, this imbalance leads to a state in which a few percent of all cells in tissues are senescent at any given time. This is, unfortunately, more than enough to produce sizable consequences to health and mortality. Senescent cells secrete a potent mix of inflammatory and growth signals that disrupt tissue function when present consistently.

Senescent cells do conduct useful, necessary activities in an environment in which they are quickly removed, and their signaling is beneficial in the short term. They assist in aspects of embryonic development, for example. The senescence of damaged and potentially cancerous cells suppresses cancer risk by efficiently removing these errant cells. Then there is the role of senescent cells in wound healing, which is the topic of today's open access paper. Wound healing captures the two-edged nature of cellular senescence in and of itself: wounds heal more rapidly in young individuals due to the presence of senescent cells. But when senescent cells are present in too great a number, they disrupt the processes of wound healing, and can give rise to non-healing wounds.

Fortunately, advances are being made in the development of therapies to selectively destroy senescent cells, or to suppress at least some of their secreted signals. I think that the former is a better strategy, as cell signaling is a very complex, poorly understood environment with many possible targets. Periodically destroying some fraction of senescent cells in a tissue reduces all of the harmful signaling, not just the part that the research community has mapped and understood. When this approach is applied to non-healing wounds, we might hope to see favorable outcomes.

Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds

The widespread causative biological effects of cellular senescence in tissue ageing pathology make the therapeutic modulation of senescence an attractive target for a plethora of age-related diseases. Genetic studies positively support this idea, with inducible knockdown of p16 alleviating hallmark features of ageing in progeroid murine models. In fact, the well-documented effects of caloric restriction, which both extends mammalian lifespan and delays the onset of age-related disease, may be a physical manifestation of tissue senescence modulation. Caloric restriction has been shown to reduce cardiac senescence, and senescence in hepatocytes and intestinal crypt cells in vivo.

A considerably more attractive proposition is the use of senescence-targeted drugs, otherwise known as senolytics. These drugs affect unique features of senescent cells, such as resistance to apoptosis. Senescent cells upregulate prosurvival pathways, particularly BCL-2. This opens up drug repurposing opportunities around the numerous BCL-2 inhibitors that were developed for the treatment of cancer. Results have been promising. Targeting BCL-2 in vivo induces apoptosis and thus eliminates senescent cells in the lung following irradiation and throughout the body following irradiation or natural ageing.

Other senolytics that have demonstrated experimental efficacy include the tyrosine kinase inhibitor, Dasatinib, used to treat leukaemia, and the flavonoid p53 activator, Quercetin. Combinatorial treatment with Dasatinib and Quercetin extends lifespan, alleviates frailty, and improves vasomotor function in aged mice. Dasatinib and Quercetin have also shown promise in a phase I trial in diabetic kidney disease patients, where reduced senescent cells and circulating SASP factors were observed following administration. Alternative flavonoids are now being tested for their potential senolytic effects, such as Fisetin, which is able to eliminate senescent cells and, crucially, restore tissue function in aged mice.

The importance of transient senescence for effective healing should not be underestimated. As noted previously, temporary induction of senescence aids rapid tissue reformation. During a normal damage response, these senescent cells are effectively cleared by natural killer cells and macrophages. Nevertheless, in chronic situations, senescent cells persist, likely due to elevated immunosenescence and resulting impaired immunological functions. It follows that treatments to boost immune system function, for instance by aiding senescent cell recognition, could be beneficial in the context of transient senescence and tissue repair. Generally, senescent cells express stimulatory ligands that bind to NK2GD receptors on natural killer cells, thus initiating a killing response. However, senescent fibroblasts in aged skin have recently been shown to express HLA-E, which bypasses recognition and clearance by natural killer and T cells. Here, approaches developed in the cancer field may also be useful, for example engineering T cells to express receptors that target specific cellular (tumour) proteins. Studies to identify and validate new senescent cell receptors will be essential to the development and clinical application of such immune-regulated approaches.

We remain a long way from implementing senescence-targeted treatments for pathological wound healing, yet it is reassuring to see that current senolytic drugs display efficacy across a wide range of tissues and pathologies. In a number of studies, systemic senolytic treatments have been shown to have clear effects in peripheral target tissues across a range of treatment regimens. For example, a single dose of BCL inhibitor, and dosing over consecutive days, was able to reverse irradiation-induced senescence in different tissues. In other work, aged mice showed improved physical performance following biweekly oral treatments of Dasatinib and Quercetin for 4 months, yet reduced SASP was observed in human ex vivo cultured adipose tissue within 48 h of treatment. Moreover, a single 3 day oral treatment of Dasatinib and Quercetin was able to reduce senescence in the adipose tissue of diabetic patients in a phase I trial. These studies therefore suggest that senolytic treatments not only have rapid effects in target peripheral tissues, but can overcome established tissue senescence.

Experimental studies do show beneficial effects of modulating senescence in the skin. For example, elimination of senescent cells from the epidermis restored proliferative capacity in hair follicle stem cells, known to participate in wound healing. Further, blockade of the potential senescence receptor, CXCR2, directly accelerated healing in human ex vivo skin wounds and diabetic murine wounds in vivo. Here, a CXCR2 antagonist was administered to wounds topically (ex vivo) and subcutaneously (in vivo), suggesting direct delivery to the wound site as a viable administration route. Indeed, elevated CXCR2 has previously been observed in diabetic wounds, and more recently in T cells from human diabetic patients. We note with interest that pharmacological inhibition of CXCR1/2 additionally prevents inflammation-mediated damage to pancreatic islets, thus prohibiting streptozocin-induced diabetes in mice. Therefore, CXCR2 appears a common factor in both the ontology and local pathology of diabetes. Senolytics should certainly be considered for the treatment of human chronic wounds characterised by high levels of senescence. However, given that knockdown of CXCR2 and ablation of senescent cells actually delays acute wound healing, future senescence-targeted therapies should be reserved for the treatment of chronic conditions.

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