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    • Human hepatocyte transplantation resulted in some animals

    2024-05-15

    Human hepatocyte transplantation resulted in some animals with relatively sparse repopulation while others had >90% of their liver containing human hepatocytes. The presence of circulating human albumin varied based on the amount of repopulation as the degree of humanization is reported to correlate with human albumin levels (1 mg/ml albumin corresponds to about 20% human hepatocyte repopulation [22]). Our previous studies with both the constitutive arginase knockout [4] and the conditional arginase knockout [7] however have shown that minimal arginase expression and ureagenesis is necessary for survival with murine arginase deficiency. Cellular transplantation with disruption of endogenous hepatocyte arginase activity did result on average in a mild increase in plasma ammonia and arginine in these repopulation studies, likely because of the incomplete repopulation of the liver with normal human hepatocytes. However, glutamine did not increase, suggesting that the ammonia metabolizing capabilities of the transplanted hepatocytes was sufficient to control normal metabolic needs. Administration of ammonium to animals was performed to provide insight on the functioning of the urea cycle to examine the capability of the transplanted hepatic mass. While we do see a marked rise in plasma ammonia at 20 min in the transplanted group compared to arginase wild type controls, behaviour is only reduced one point and animals regained normal activity quickly. Furthermore, at 1 h, plasma ammonia had declined nearly 50%. Importantly, this reduces the nitrogen vulnerability of these animals; in our previous studies with the constitutive arginase knockout treated with AAV, there was tremendous episomal vector loss, and with ammonium challenging, there was high plasma ammonia at 1 h, with associated marked reduced behavioral scores, hypothermia, with subsequent seizures and death [5]. The following are the supplementary data related to this article.
    Acknowledgements The authors thank Lisa Wilson PhD (Yecuris) for helpful discussions in the course of this work. Amino Uridine receptor profiles were performed in the Metabolomics Core facility, The Children's Hospital of Philadelphia (https://metabolomic.research.chop.edu/) and the authors thank Itzhak and Ilana Nissim for performing these analyses. This work was supported by the California Institute for Regenerative Medicine (grant number TR4-06831 to GSL), the National Institutes of Health (grant number 5 R01 NS100979-01 to GSL and grant number 5T32GM08243-29 to SAKA), and the American Liver Foundation (Roger L. Jenkins, MD Postdoctoral Research Fellowship Award to SAKA).
    Introduction Erectile dysfunction (ED) is a common disease that impacts health and social aspects of affected patients [1]. This multifactorial disease [2] has different etiologic origins including neurogenic, vasculogenic, and endocrine mechanisms [3]. Vasculogenic ED is commonly associated with cardiovascular diseases (CVD) [4], [5] and patients with CVD are exposed to increased risk of developing ED [6]. Indeed, ED is now considered an early marker for future CVD [4] because it reflects endothelial dysfunction and impaired relaxation of smooth muscle cells [7] in patients with ED and CVD. Nitric oxide (NO) is one of the most important molecules involved in the physiology of erection and its bioactivity usually decreases in CVD [2], [8]. While this molecule is produced by three different isoforms of NO synthases (NOS), two isoforms (endothelial and neuronal NOS, eNOS and nNOS, respectively) are considered of paramount importance for normal erectile function [2], [9], [10], [11], [12], [13]. All NOS enzymes utilize l-arginine as substrate for NO synthesis [2], [11]. However, this substrate is also used by other enzymes ubiquitously expressed in the body, Arginase 1 and Arginase 2 [11], which consume l-arginine producing l-ornithine and urea [14], [15]. They are expressed in the corpus cavernosum [16], [17], [18] and co-localize with eNOS in the endothelium [19]. Importantly, Arginases 1 and 2 compete with NOS for l-Arginine, and therefore the higher the arginase activity, the lower the NO production will be as a result of local microenvironmental substrate exhaustion [14], [15], [20], [21]. This competition has already been shown in several different conditions [15], [20], [21], [22], [23] including experimental erectile dysfunction [24], [25]. Furthermore, inhibition of Arginase activity improved erectile function in animal models of ED [18], [24], [26], [27], [28], [29]. Since NO is the main molecule responsible for starting and maintaining erection, and its production is reduced in ED [2], it is possible that increased arginase expression or activity contribute to the pathogenesis of ED.