Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration Natarajan N, Abbas Y, Bryant DM, et al. Circulation. 2018;137:2152-2165. The organ shortage is perhaps the most pressing challenge facing the modern field of transplantation. Several approaches are being actively pursued to address this dilemma, including publicity drives to enhance donation rates, paired exchange donation, and an expanded use of marginal donor organs as well as their preconditioning. However, as the burden of organ failure increases, it is not entirely clear whether these approaches will fully address the organ shortage. Over the past decade, experimental techniques have focused on xenotransplantation and regenerative medicine to provide a supply of healthy organs or to repair endogenous organs. These approaches are now starting to gain traction as potentially realistic solutions1. In comparison to most organs, the heart has poor regenerative capabilities. Nevertheless, neonates in addition to some other animals, such as axolotl (also known as the Mexican Salamander) and zebrafish demonstrate enhanced cardiac regenerative ability in comparison to adult mammals. In a study from Natarajan and coworkers published in Circulation, a transcriptomic screen was performed across axolotl, zebrafish and mice to assess the molecular pathways that may be involved in their cardiac regenerative ability2. Ventricular apical resection was performed at various time points and RNA isolated from a section of the ventricle that remained in situ. RNA sequencing revealed an upregulation in inflammatory process genes. In particular, complement 5a receptor 1 (C5aR1) was found to be upregulated in all 3 species. In vivo inhibition of C5aR1 using a highly selective antagonist (PMX205) or genetic knockout significantly attenuated cardiomyocyte proliferation. C5aR1 is activated by complement 5a (C5a), and this pathway is an established innate immune activator. Interestingly, C5a has also previously been shown to be relevant in mouse liver regeneration3. Nevertheless, the authors found that treatment with C5a in vitro did not enhance cardiomyocyte proliferation, whereas in vivo treatment produced only a marginal increase in cardiomyocyte proliferation. Whether this pathway truly defines a specific therapeutic target remains unclear. However, the methodology in this article and the RNA-sequencing data (which has been deposited publicly) may reveal some of the mechanisms relevant to cardiac regeneration and provide useful insights for the regenerative medicine field. REFERENCES Pierson RN 3rd. Brief Summary Report From the 14th Biennial Meeting of the International Xenotransplantation Association. Transplantation. 2018;102:757–759. Natarajan N, Abbas Y, Bryant DM, et al. Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration. Circulation. 2018;137:2152–2165. Strey CW, Markiewski M, Mastellos D, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med. 2003;198:913–923. De Novo Formation of the Biliary System by TGBβ-mediated Hepatocyte Transdifferentiation Schaub JR, Hupper KA, Kurial SNT, et al. [published online May 2, 2018]. Nature. DOI: 10.1038/s41586-018-0075-5. In contrast to stem cell–mediated regeneration, transdifferentiation is defined as a cellular plasticity that allows a change in cell identity as an alternative method for specific cellular replacement.1 An organ with inherent regenerative capabilities is the liver. In response to injury, hepatocytes undergo transdifferentiation to form biliary ductules, although it is thought that these do not form functional bile ducts, with ductiles reverting to a hepatocyte phenotype after injury resolution. A question therefore remains over whether this process is metaplasia rather than transdifferentiation, particularly because it is of unknown physiological relevance. In the second study in this month's Research Highlights, this question is addressed by Schaub and co-workers in the May 2018 issue of Nature.2 In contrast to previous studies, the study used a model where mice have severe cholestasis due to a lack of peripheral bile ducts, mimicking human Alagille syndrome, therefore allowing an accurate assessment of the functional capacity of transdifferentiated hepatocytes. Using fate-tracing assays, the authors found that hepatocytes do indeed differentiate into functional cholangiocytes that form de novo bile ducts which are functionally able to drain bile and persist after the liver injury is reversed. This hepatocyte plasticity therefore represents transdifferentiation rather than metaplasia. Through RNA sequencing gene ontology analysis, TGFβ signaling was found to be active in transdifferentiated cholangiocytes. Inhibition of TGFβ signaling prevented bile duct transdifferentiation, whereas activation of TGFβ signaling (using a specific vector) enhanced hepatocyte-derived bile duct formation. Interestingly, in liver samples derived from patients with Alagille syndrome, evidence for TGFβ signaling in peripheral bile ducts was confirmed by detection of nuclear pSMAD3. These mechanisms and the identification of TGFβ signaling as a potential therapeutic target represent fascinating leads for furthering our understanding the process of liver regeneration. REFERENCES Merrell AJ, Stanger BZ. Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol. 2016;17:413–425. Schaub JR, Huppert KA, Kurial SNT, et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. [Published online May 2, 2018]. Nature. DOI:10.1038/s41586-018-0075-5.
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Aug 9, 2019
Sungjin Ko + 3
