The carotid body: a physiologically relevant germinal niche in the adult peripheral nervous system

Oxygen constitutes a vital element for the survival of every single cell in multicellular aerobic organisms like mammals. A complex homeostatic oxygen-sensing system has evolved in these organisms, including detectors and effectors, to guarantee a proper supply of the element to every cell. The carotid body represents the most important peripheral arterial chemoreceptor organ in mammals and informs about hypoxemic situations to the effectors at the brainstem cardiorespiratory centers. To optimize organismal adaptation to maintained hypoxemic situations, the carotid body has evolved containing a niche of adult tissue-specific stem cells with the capacity to differentiate into both neuronal and vascular cell types in response to hypoxia. These neurogenic and angiogenic processes are finely regulated by the niche and by hypoxia itself. Our recent data on the cellular and molecular mechanisms underlying the functioning of this niche might help to comprehend a variety of different diseases coursing with carotid body failure, and might also improve our capacity to use these stem cells for the treatment of neurological disease. Herein, we review those data about the recent characterization of the carotid body niche, focusing on the study of the phenotype and behavior of multipotent stem cells within the organ, comparing them with other well-documented neural stem cells within the adult nervous system

Generation of human organs in pigs via interspecies blastocyst complementation

More than eighteen years have passed since the first derivation of human embryonic stem cells (ESCs), but their clinical use is still met with several challenges, such as ethical concerns regarding the need of human embryos, tissue rejection after transplantation and tumour formation. The generation of human induced pluripotent stem cells (iPSCs) enables the access to patient-derived pluripotent stem cells (PSCs) and opens the door for personalized medicine as tissues/organs can potentially be generated from the same genetic background as the patient recipients, thus avoiding immune rejections or complication of immunosuppression strategies. In this regard, successful replacement, or augmentation, of the function of damaged tissue by patient-derived differentiated stem cells provides a promising cell replacement therapy for many devastating human diseases. Although human iPSCs can proliferate unlimitedly in culture and harbour the potential to generate all cell types in the adult body, currently, the functionality of differentiated cells is limited. An alternative strategy to realize the full potential of human iPSC for regenerative medicine is the in vivo tissue generation in large animal species via interspecies blastocyst complementation. As this technology is still in its infancy and there remains more questions than answers, thus in this review, we mainly focus the discussion on the conceptual framework, the emerging technologies and recent advances involved with interspecies blastocyst complementation, and will refer the readers to other more in-depth reviews on dynamic pluripotent stem cell states, genome editing and interspecies chimeras. Likewise, other emerging alternatives to combat the growing shortage of human organs, such as xenotransplantation or tissue engineering, topics that has been extensively reviewed, will not be covered here

Interspecies Chimerism with Mammalian Pluripotent Stem Cells

Interspecies blastocyst complementation enables organ-specific enrichment of xenogenic pluripotent stem cell (PSC) derivatives. Here, we establish a versatile blastocyst complementation platform based on CRISPR-Cas9-mediated zygote genome editing and show enrichment of rat PSC-derivatives in several tissues of gene-edited organogenesis-disabled mice. Besides gaining insights into species evolution, embryogenesis, and human disease, interspecies blastocyst complementation might allow human organ generation in animals whose organ size, anatomy, and physiology are closer to humans. To date, however, whether human PSCs (hPSCs) can contribute to chimera formation in non-rodent species remains unknown. We systematically evaluate the chimeric competency of several types of hPSCs using a more diversified clade of mammals, the ungulates. We find that naïve hPSCs robustly engraft in both pig and cattle pre-implantation blastocysts but show limited contribution to post-implantation pig embryos. Instead, an intermediate hPSC type exhibits higher degree of chimerism and is able to generate differentiated progenies in post-implantation pig embryos

Progenitor cell heterogeneity in the adult carotid body germinal niche

Somatic stem cells confer plasticity to adult tissues, permitting their maintenance, repair and adaptation to a changing environment. Adult germinal niches supporting somatic stem cells have been thoroughly characterized throughout the organism, including in central and peripheral nervous systems. Stem cells do not reside alone within their niches, but they are rather accompanied by multiple progenitor cells that not only contribute to the progression of stem cell lineage but also regulate their behavior. Understanding the mechanisms underlying these interactions within the niche is crucial to comprehend associated pathologies and to use stem cells in cell therapy. We have described a stunning germinal niche in the adult peripheral nervous system: the carotid body. This is a chemoreceptor organ with a crucial function during physiological adaptation to hypoxia. We have shown the presence of multipotent stem cells within this niche, escorted by multiple restricted progenitor cell types that contribute to niche physiology and hence organismal adaptation to the lack of oxygen. Herein, we discuss new and existing data about the nature of all these stem and progenitor cell types present in the carotid body germinal niche, discussing their role in physiology and their clinical relevance for the treatment of diverse pathologies.Peer reviewe