Human induced pluripotent stem cells (iPSCs) promise to revolutionize research and therapy of liver diseases by providing a source of hepatocytes for autologous cell therapy and disease modeling. However, despite progress in advancing the differentiation of iPSCs into hepatocytes (iPSC-Heps) in vitro1–3, cells that replicate the ability of human primary adult hepatocytes (aHeps) to proliferate extensively in vivo have not been reported. This deficiency has hampered efforts to recreate human liver diseases in mice, and has cast doubt on the potential of iPSC-Heps for liver cell therapy. The reason is that extensive post-transplant expansion is needed to establish and sustain a therapeutically effective liver cell mass in patients, a lesson learned from clinical trials of aHep transplantation4. As a solution to this problem, we report generation of human fibroblast-derived hepatocytes that can repopulate mouse livers. Unlike current protocols for deriving hepatocytes from human fibroblasts, ours did not generate iPSCs, but shortcut reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells (iMPC-EPCs) and subsequently hepatocytes (iMPC-Heps) could be efficiently differentiated. For this, we identified small molecules that aided endoderm and hepatocyte differentiation without compromising proliferation. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to aHeps. Unfractionated iMPC-Heps did not form tumors, most likely because they never entered a pluripotent state. To our knowledge, this is the first demonstration of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

Donation after cardiac death (DCD) and acute kidney injury (AKI) donors have historically been considered independent risk factors for delayed graft function (DGF), allograft failure, and inferior outcomes. With growing experience, updated analyses have shown good outcomes. There continues to be limited data, however, on outcomes specific to DCD donors who have AKI. Primary outcomes for this study were post–kidney transplant patient and allograft survival comparing two donor groups: DCD AKIN stage 2‐3 and DBD AKIN stage 2‐3. In comparing these groups, there were no short‐ or long‐term differences in patient (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.54‐1.93, P = .83) or allograft survival (HR 1.47, 95% CI 0.64‐2.97, P = .32). In multivariate models, the DCD/DBD status had no significant impact on the estimated GFR (eGFR) at 1 (P = .38), 2 (P = .60), and 3 years (P = .52). DGF (57.9% vs 67.9%, P = .09), rejection (12.1% vs 13.9%, P = .12), and progression of interstitial fibrosis/tubular atrophy (IFTA) on protocol biopsy (P = .16) were similar between the two groups. With careful selection, good outcomes can be achieved utilizing severe AKI DCD kidneys. Historic concerns regarding primary nonfunction, DGF resulting in interstitial fibrosis and rejection, and inferior outcomes were not observed. Given the ongoing organ shortage, increased effort should be undertaken to further utilize these donors.

In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate.

Background This report examines the surgical safety and complications (SC) among 125 liver (L) and 150 kidney (K) HIV+ transplant (TX) recipients in a prospective non-randomized US multicenter trial. Methods Subjects required CD4+ T-cell count > 200/100 cells/mm3 (K/L) & undetectable plasma HIV-1 RNA (VL) (K) or expected post-transplant suppression (L). Impact of SCs (N≥7) was evaluated using proportional hazards (PH) models. Baseline morbidity predictors for SCs (N≥7) were assessed in univariate PH models. Results At median 2.7 [interquartile range (IQR) 1.9, 4.1] & 2.3 [1.0, 3.7] years post- TX, 3-month & 1-year graft survival were [K] 96% (CI 91%,98%) & 91% (85%,94%) & [L] 91% (85%,95%) & 77% (69%,84%). 14K and 28L graft losses occurred in the first year; 6K and 11L were in the first 3 months. 26(17%) K and 43 (34%) L experienced 29 and 62 SCs, respectively. In the liver multivariate model, re-exploration was marginally associated (HR: 2.8; 95% CI: 1.0-8.4; p=0.06) with increased risk of graft loss, while higher MELD pre-transplant (HR: 1.07 per point increase; 95% CI: 1.01-1.14; p=0.02), and detectable viral load pre-TX (HR: 3.6; 95% CI: 0.9-14.6; p=0.07) was associated with an increased risk of wound infections/dehiscence. Conclusions The rates and outcomes of surgical complications are similar to what has been observed in the non-HIV setting in carefully selected HIV-infected liver and kidney TX recipients.