Acute respiratory distress syndrome (ARDS) in COVID‐19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti‐inflammatory effects and could yield beneficial effects in COVID‐19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC‐MSC) infusions in subjects with COVID‐19 ARDS. A double‐blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty‐four subjects were randomized 1:1 to either UC‐MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC‐MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC‐MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion‐associated AEs. No serious adverse events (SAEs) were observed related to UC‐MSC infusions. UC‐MSC infusions in COVID‐19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC‐MSC‐treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE‐free survival (P = .008), and time to recovery (P = .03). UC‐MSC infusions are safe and could be beneficial in treating subjects with COVID‐19 ARDS.

Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (HEPATOLOGY 2016;64:277-286)

Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG,OCT4,SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9,SOX17,PDX1,LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3,MUC6,insulin). Radial-axis lineages start in PBGs near the ducts’ fibromuscular layers with stem cells and end at the ducts’ lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes. Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, culture plastic and serum-free Kubota’s Medium, proliferating for months as undifferentiated cells, whereas pancreas-derived cells underwent only ∼8-10 divisions, then partially differentiated towards an islet fate. Biliary tree-derived cells proved precursors of pancreas’ committed progenitors. Both could be driven by 3-dimensional conditions, islet-derived matrix components and a serum-free, hormonally defined medium for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neoislets, including glucose regulatability. Implantation of these neoislets into epididymal fat pads of immuno-compromised mice, chemically rendered diabetic, resulted in secretion of human C-peptide, regulatable by glucose, and able to alleviate hyperglycemia in hosts. The biliary tree-derived stem cells and their connections to pancreatic committed progenitors constitute a biological framework for life-long pancreatic organogenesis.