Cardiomyocytes can be implanted to remuscularize the failing heart^1–7. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques. After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation⁸, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed. The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.

Baboons (genus Papio ) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high-coverage whole-genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and interspecies gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes.

Many mammal species have declining populations, but the consequences of small population size on the genomic makeup of species remain largely unknown. We investigated the evolutionary history, genetic load and adaptive potential of the Cat Ba langur (Trachypithecus poliocephalus), a primate species endemic to Vietnam’s famous Ha Long Bay and with less than 100 living individuals one of the most threatened primates in the world. Using high-coverage whole genome data of four wild individuals, we revealed the Cat Ba langur as sister species to its conspecifics of the northern limestone langur clade and found no evidence for extensive secondary gene flow after their initial separation. Compared to other primates and mammals, the Cat Ba langur showed low levels of genetic diversity, long runs of homozygosity, high levels of inbreeding and an excess of deleterious mutations in homozygous state. On the other hand, genetic diversity has been maintained in protein-coding genes and on the gene-rich human chromosome 19 ortholog, suggesting that the Cat Ba langur retained most of its adaptive potential. The Cat Ba langur also exhibits several unique non-synonymous variants that are related to calcium and sodium metabolism, which may have improved adaptation to high calcium intake and saltwater consumption.

Understanding how organisms adapt to their environments is a central question in evolutionary biology. Limestone langurs are unique among primates, as they are exclusively found in karst limestone habitats and have evolved mechanisms to tolerate high levels of mineral ions, which are typically associated with metal toxicity affecting organs, cells, and genetic material. We generated a high-quality reference genome (Tfra_5.0) for the limestone langur (Trachypithecus francoisi), along with genome resequencing data for 48 langurs representing 15 Trachypithecus species. Genes encoding ion channels (e.g., Na+, K+, and Ca2+) exhibited significantly accelerated evolution in limestone langurs. Limestone langur-specific mutations in Na+ and Ca2+ channels were experimentally confirmed to modify inward ion currents in vitro. Unexpectedly, scans for positive selection also identified genes involved in DNA damage response/repair pathways, a previously unknown adaptation. This finding highlights an evolutionary adaptation in limestone langurs that mitigates the increased risk of DNA damage posed by elevated metal ion concentrations. Notably, a limestone langur-specific mutation (E94D) of the melanocortin 1 receptor (MC1R) was associated with increased basal cyclic adenosine monophosphate (cAMP) production, contributing to the species’ darker coat color, which likely serves as camouflage on limestone rocks. Our findings reveal novel adaptive evolutionary mechanisms of limestone langurs and offer broader insights into organismal adaptation to extreme environments, with potential implications for understanding human health, biological evolution, and biodiversity conservation.

Background/Objective: The Bale monkey (Chlorocebus djamdjamensis) is a threatened primate species endemic to Ethiopia and, in contrast to other members of the genus Chlorocebus, lives at high altitudes and feeds mainly on bamboo. Two populations of the species are present, one in continuous bamboo forest (CF) in the eastern part of the species’ range, and the other in fragmented forest (FF) in the western part. Based on mitochondrial DNA and phenotypic characteristics, previous studies have suggested introgression by parapatric congeners into the FF population but not into the CF population. The objective of this study was to gain insights into the evolutionary history of Bale monkeys and their potential genetic adaptations to high altitudes and for bamboo consumption. Methods: We sequenced the whole genomes of individuals from both populations and compared their genomes with those of the other five Chlorocebus species. We applied phylogenetic methods and conducted population demographic simulations to elucidate their evolutionary history. A genome-wide analysis was conducted to assess gene flow and identify mutations potentially associated with adaptations to high altitudes and for bamboo metabolism. Results: Our analyses revealed Bale monkeys as the sister clade to Chlorocebus aethiops and showed that gene flow occurred between C. aethiops and FF but not between C. aethiops and CF. In addition, we detected non-synonymous mutations in genes potentially associated with the adaptation to high altitudes (EPAS1) in both populations and with the adaptation for bamboo metabolism (TAS2R16, MPST, and TST) mainly in the CF population. Conclusions: Our study provides insights into the evolutionary history of a threatened primate species and reveals the genetic basis for its adaptions to unique environments and for diet specialization.