In recent decades, the Hedgehog signal cascade has been in the focus of experimental investigations establishing that this highly conserved pathway plays an important role in embryonic development and morphogenesis 1. Since its first recognition in Drosophila our understanding of the high-level process of tissue maintenance during physiological regeneration and repair has dramatically increased 2. These insights have successfully been translated to human cancerogenesis 3. As detailed in reviews and experimentally shown by our group, genetically deregulated or ectopic overexpression of the Hedgehog signaling cascade can be detected in many human malignancies at both early and late phases of cancerogenesis. This suggests ubiquitous distribution of this highly preserved pathway in cancer 4–6. However, the relationship of the Hedgehog pathway to senescence and chronic degenerative and inflammatory diseases of the elderly has, until recently, received much less attention. But the associated processes of regeneration and repair of these chronic inflammatory diseases have revealed a similar repertoire of basic molecular pathways, including the Hedgehog signaling cascade 7. In summary, the “chronological” status of Hedgehog signaling integrity seems to continuously decline from development to carcinogenesis, whereas during the interjacent time phase of aging, degeneration could be characterized by the lowest Hedgehog pathway activity, as schematically illustrated in Fig. 1. However, the network of the interacting driving forces is unclear.
The increase in age-related diseases such as neurodegenerative diseases or atherosclerosis (a result of the growing elderly population in the Western world) demands “innovative” or “alternative” approaches to preventing, or at least slowing down, disease progression and ensuing complications.
In this issue of BioEssays Dashti et al. present the interesting hypothesis that Hedgehog signaling could essentially act as an antagonist of aging processes and associated diseases such as atherosclerosis, osteoporosis, skin aging, and neurodegenerative diseases 8. In support of their provocative hypothesis, the authors give a complete, accurate, and detailed survey of the Hedgehog pathway in general, and of its possible role in aging and associated diseases. But what is so remarkable about this hypothesis? Let us have a detailed look at this hitherto unexpected face of the Hedgehog signaling pathway:
- (i)As senescence depends on the integrity of the stem cell compartment, and the Hedgehog pathway could influence the stemness of cells in tissue differentiation, it is obvious to connect senescence and the Hedgehog pathway. One compelling argument for that hypothesis emanates from a genome-wide siRNA analysis of p16INK4a. This experiment showed that the Gli-2 transcription factor of the Hedgehog pathway is able to inhibit the p16 (Ink4) promoter, one of the key players of senescence, especially in the stem cell compartment 9. The critical insight is that cellular downstream activity of the Hedgehog cascade depends on three different Gli transcription factors interacting with each other 10, which are influenced by a variety of other classical pathways such as WNT, TGF-β, or BMP for example 4. This leads to a non-transparent, canonical, and non-canonical molecular network.
- (ii)When looking at the afore-mentioned chronic diseases such as osteoporosis, neurodegenerative syndromes, skin aging, and atherosclerosis, a common denominator between disease pathogenesis and the Hedgehog pathway could be determined: Hedgehog-associated stem cell recruitment is not only involved in skin aging, but also in neurodegenerative diseases, whereas the Hedgehog signaling pathway influences differentiation only in osteoporosis, as shown in experimental settings. Interestingly, differentiation of primary mesenchymal stem cells can be used for tissue cartilaginous engineering via IHH gene delivery, as recently published 11. Finally, members of the Hedgehog family show angiogenesis and anti-apoptotic capacity in atherosclerosis and neurodegenerative syndromes, and thus improve tissue survival – a concept that was proven by Hedgehog gene transfer experiments in cardio-vascular diseases 12. Dashti and colleagues point out that the functional activity of the Hedgehog pathway is essentially influenced by sterol metabolism being deregulated in metabolic syndrome of elderly patients. This could explain arterial disease progression in hypercholesterolemia patients 13. Additionally, a competitive receptor crosslink between hyperglycemia and Hedgehog signaling connects pathogenic observations in osteoporosis and atherosclerosis, indicating the pleiotropic/systemic effects of a disturbed metabolic homoeostasis on Hedgehog integrity and pathway activity (see Fig. 1).
Taken together, Dashti and colleagues present an interesting, novel and intriguing view of another part of Hedgehog signaling in humans, which has been overlooked until now, and which should be thoroughly discussed in the scientific community.
Nevertheless, numerous questions need to be answered regarding potential future therapeutic interventions:
- (i)How could we activate or stabilize the Hedgehog pathway without activating its unwanted effects in human cancerogenesis 14?
- (ii)How could we clarify the Gli code to understand the activating and repressing functionality of the Gli proteins inside the Hedgehog signaling pathway 10?
- (iii)How could we exploit the non-canonical mechanism 15 to specifically activate the Hedgehog signaling pathway to prevent senescence and its associated chronic degenerative diseases?
- (iv)Which role do the lipoprotein transfer system, as well as adipocyte compartment, play for the highly hydrophobic and sterolated Hedgehog molecules 16?
The contest is open for novel approaches and experiments to gain more insight into this sophisticated, new and unknown face of the Hedgehog signaling cascade in regenerative and reparative medicine. The hope is that this will lead to the identification of new therapeutic targets.