Beneficial Effects of Two Marine Oxygen Carriers, M101 and M201, on Human Islet Quality in Hypoxic Culture Conditions.

High pancreatic islet sensitivity to hypoxia is an important issue in the field of pancreatic islet transplantation. A promising strategy to improve islet oxygenation in hypoxic conditions is to leverage the properties of hemoglobin as a natural carrier of oxygen. Studies using human or bovine hemoglobin have failed to demonstrate efficacy, probably due to the molecule being unstable in the absence of protective erythrocytes. Recently, marine worm hemoglobins have been shown to be more stable and to possess higher oxygen carrier potential, with 156 oxygen binding sites per molecule compared to four in humans. Previous studies have shown the beneficial effects of two marine worm hemoglobins, M101 and M201, on nonhuman pancreatic islets. However, their effects on human islets have not been tested or compared. In this study, we assessed the impact of both molecules during human islet culture in vitro under hypoxic conditions. Human islets were exposed to both molecules for 24 h in high islet density-induced hypoxia [600 islet equivalents (IEQ)/cm²]. M101 and M201 reduced the release of hypoxic (VEGF) and apoptotic (cyt c) markers in the medium after 24-h culture. Human islet function or viability was improved in vitro in the presence of these oxygen carriers. Thus, the utilization of M101 or M201 could be a safe and easy way to improve human islet oxygenation and survival in hypoxic conditions as observed during islet culture prior to transplantation or islet encapsulation.

Recapitulating macro-scale tissue self-organization through organoid bioprinting.

Bioprinting promises enormous control over the spatial deposition of cells in three dimensions1-7, but current approaches have had limited success at reproducing the intricate micro-architecture, cell-type diversity and function of native tissues formed through cellular self-organization. We introduce a three-dimensional bioprinting concept that uses organoid-forming stem cells as building blocks that can be deposited directly into extracellular matrices conducive to spontaneous self-organization. By controlling the geometry and cellular density, we generated centimetre-scale tissues that comprise self-organized features such as lumens, branched vasculature and tubular intestinal epithelia with in vivo-like crypts and villus domains. Supporting cells were deposited to modulate morphogenesis in space and time, and different epithelial cells were printed sequentially to mimic the organ boundaries present in the gastrointestinal tract. We thus show how biofabrication and organoid technology can be merged to control tissue self-organization from millimetre to centimetre scales, opening new avenues for drug discovery, diagnostics and regenerative medicine.

Engineering Stem Cell Self-organization to Build Better Organoids.

Organoids form through self-organization processes in which initially homogeneous populations of stem cells spontaneously break symmetry and undergo in-vivo-like pattern formation and morphogenesis, though the processes controlling this are poorly characterized. While these in vitro self-organized tissues far exceed the microscopic and functional complexity obtained by current tissue engineering technologies, they are non-physiological in shape and size and have limited function and lifespan. Here, we discuss how engineering efforts for guiding stem-cell-based development at multiple stages can form the basis for the assembly of highly complex and rationally designed self-organizing multicellular systems with increased robustness and physiological relevance.

Hutchinson-Gilford progeria syndrome as a model for vascular aging.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a de novo genetic mutation that leads to the accumulation of a splicing isoform of lamin A termed progerin. Progerin expression alters the organization of the nuclear lamina and chromatin. The life expectancy of HGPS patients is severely reduced due to critical cardiovascular defects. Progerin also accumulates in an age-dependent manner in the vascular cells of adults that do not carry genetic mutations associated with HGPS. The molecular mechanisms that lead to vascular dysfunction in HGPS may therefore also play a role in vascular aging. The vascular phenotypic and molecular changes observed in HGPS are strikingly similar to those seen with age, including increased senescence, altered mechanotransduction and stem cell exhaustion. This article discusses the similarities and differences between age-dependent and HGPS-related vascular aging to highlight the relevance of HGPS as a model for vascular aging. Induced pluripotent stem cells derived from HGPS patients are suggested as an attractive model to study vascular aging in order to develop novel approaches to treat cardiovascular disease.