Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry

Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long-term neuroepithelial-like stem (lt-NES) cell-derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke-injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all studies with human pluripotent stem cell-derived neurons have been carried out using xenotransplantation in animal models. Whether these neurons can integrate also into adult human brain circuitry is unknown. Here, we show that cortically fated lt-NES cells, which are able to form functional synaptic networks in cell culture, differentiate to mature, layer-specific cortical neurons when transplanted ex vivo onto organotypic cultures of adult human cortex. The grafted neurons are functional and establish both afferent and efferent synapses with adult human cortical neurons in the slices as evidenced by immuno-electron microscopy, rabies virus retrograde monosynaptic tracing, and whole-cell patch-clamp recordings. Our findings provide the first evidence that pluripotent stem cell-derived neurons can integrate into adult host neural networks also in a human-to-human grafting situation, thereby supporting their potential future clinical use to promote recovery by neuronal replacement in the patient's diseased brain

Translating weight loss into agency: Men’s experiences 5 years after bariatric surgery

Fewer men than women with severe obesity undergo bariatric surgery for weight loss, and knowledge about men's situation after surgery, beyond medical status, is lacking. Our aim was to explore men's experiences with life after bariatric surgery from a long-term perspective. We conducted in-depth interviews with 13 men, aged 28–60 years, between 5 and 7 years after surgery. The analysis was inspired by Giorgi's phenomenological method. We found that agency was pivotal for how the men understood themselves and their lives after surgery. Weight loss meant regaining opportunities for living and acting in unrestricted and independent daily lives, yet surgery remained a radical treatment with complex consequences. Turning to surgery had involved conceptualizing their own body size as illness, which the men had resisted doing for years. After surgery, the rapid and major weight loss and the feelings of being exhausted, weak, and helpless were intertwined. The profound intensity of the weight loss process took the men by surprise. Embodying weight loss and change involved an inevitable renegotiating of experiences connected to the large body. Having bariatric surgery was a long-term process that seemed unfinished 5 years after surgery. Restrictions and insecurity connected to health and illness persist, despite successful weight loss and embodied change. Bariatric surgery initiated a complex and long-lasting life-changing process, involving both increased capacity for agency and illness-like experiences

Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots

Adipocyte function is a major determinant of metabolic disease, warranting investigations of regulating mechanisms. We show at single-cell resolution that progenitor cells from four human brown and white adipose depots separate into two main cell fates, an adipogenic and a structural branch, developing from a common progenitor. The adipogenic gene signature contains mitochondrial activity genes, and associates with genome-wide association study traits for fat distribution. Based on an extracellular matrix and developmental gene signature, we name the structural branch of cells structural Wnt-regulated adipose tissue-resident (SWAT) cells. When stripped from adipogenic cells, SWAT cells display a multipotent phenotype by reverting towards progenitor state or differentiating into new adipogenic cells, dependent on media. Label transfer algorithms recapitulate the cell types in human adipose tissue datasets. In conclusion, we provide a differentiation map of human adipocytes and define the multipotent SWAT cell, providing a new perspective on adipose tissue regulation.ISSN:2522-581