Biomanufacturing in low Earth orbit for regenerative medicine.

Research in low Earth orbit (LEO) has become more accessible. The 2020 Biomanufacturing in Space Symposium reviewed space-based regenerative medicine research and discussed leveraging LEO to advance biomanufacturing for regenerative medicine applications. The symposium identified areas where financial investments could stimulate advancements overcoming technical barriers.

CIRM tools and technologies: Breaking bottlenecks to the development of stem cell therapies.

The California Institute for Regenerative Medicine (CIRM) has a mission to accelerate stem cell treatments to patients with unmet medical needs. This perspective describes successful examples of work funded by CIRM's New Cell Lines and Tools and Technologies Initiatives, which were developed to address bottlenecks to stem cell research and translation. The tools developed through these programs evolved from more discovery-oriented technologies, such as disease models, differentiation processes, and assays, to more translation focused tools, including scalable good manufacturing processes, animal models, and tools for clinical cell delivery.

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies.

Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life-threatening complications from transplant.

Proceedings: the SEED grant program: a brief synopsis of the outcomes and impact of CIRM's first research initiative.

In late 2006, the California Institute for Regenerative Medicine (CIRM) launched its first major research initiative to catalyze the nascent field of human embryonic stem cell (hESC) research at a time when federal funding of such studies was severely restricted. This Scientific Excellence through Exploration and Development (SEED) grant program supported a portfolio of scientific endeavors ranging from the most fundamental studies of hESC biology and behavior to exploring the therapeutic potential and value of these cells as tools of biomedical innovation. The SEED program attracted new investigators from all stages of their career into the field of hESC research, many of whom continue to pursue related studies through CIRM's ongoing research and development programs or with the support of other funding organizations.

Proceedings: Immune Tolerance and Stem Cell Transplantation: A CIRM Mini-Symposium and Workshop Report.

The mission of the California Institute for Regenerative Medicine (CIRM) is to accelerate stem cell treatments to patients with unmet medical needs. Immune rejection is one hurdle that stem cell therapies must overcome to achieve a durable and effective therapeutic benefit. In July 2014, CIRM convened a group of clinical investigators developing stem cell therapeutics, immunologists, and transplantation biologists to consider strategies to address this challenge.

Proceedings: consideration of genetics in the design of induced pluripotent stem cell-based models of complex disease.

The goal of exploiting induced pluripotent stem cell (iPSC) technology for the discovery of new mechanisms and treatments of disease is being pursued by many laboratories, and analyses of rare monogenic diseases have already provided ample evidence that this approach has merit. Considering the enormous medical burden imposed by common chronic diseases, successful implementation of iPSC-based models has the potential for major impact on these diseases as well. Since common diseases represent complex traits with varying genetic and environmental contributions to disease manifestation, the use of iPSC technology poses unique challenges.

Bottlenecks in deriving definitive hematopoietic stem cells from human pluripotent stem cells: a CIRM mini-symposium and workshop report.

On August 29, 2013, the California Institute for Regenerative Medicine (CIRM) convened a small group of investigators in San Francisco, CA, to discuss a longstanding challenge in the stem cell field: the inability to derive fully functional, definitive hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs). To date, PSC-derived HSCs have been deficient in their developmental potential and their ability to self-renew and engraft upon transplantation. Tasked with identifying key challenges to overcoming this "HSC bottleneck", workshop participants identified critical knowledge gaps in two key areas: (a) understanding the ontogeny of human HSCs, and (b) understanding of the intrinsic and extrinsic factors that govern HSC behavior and function.

Return of results in translational iPS cell research: considerations for donor informed consent.

Efforts have emerged internationally to recruit donors with specific disease indications and to derive induced pluripotent cell lines. These disease-specific induced pluripotent stem cell lines have the potential to accelerate translational goals such as drug discovery and testing. One consideration for donor recruitment and informed consent is the possibility that research will result in findings that are clinically relevant to the cell donor.

Human disease modeling with induced pluripotent stem cells.

In the past few years, cellular programming, whereby virtually all human cell types, including those deep within the brain or internal organs, can potentially be produced and propagated indefinitely in culture, has opened the door to a new type of disease modeling. Importantly, many diseases or disease predispositions have genetic components that vary from person to person. Now cells from individuals can be readily reprogrammed to form pluripotent cells, and then directed to differentiate into the lineage and the cell type in which the disease manifests.

Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p.

Mgm1p is a conserved dynamin-related GTPase required for fusion, morphology, inheritance, and the genome maintenance of mitochondria in Saccharomyces cerevisiae. Mgm1p undergoes unconventional processing to produce two functional isoforms by alternative topogenesis. Alternative topogenesis involves bifurcate sorting in the inner membrane and intramembrane proteolysis by the rhomboid protease Pcp1p.

Unbiased selection of localization elements reveals cis-acting determinants of mRNA bud localization in Saccharomyces cerevisiae.

Cytoplasmic mRNA localization is a mechanism used by many organisms to generate asymmetry and sequester protein activity. In the yeast Saccharomyces cerevisiae, mRNA transport to bud tips of dividing cells is mediated by the binding of She2p, She3p, and Myo4p to coding regions of the RNA. To date, 24 bud-localized mRNAs have been identified, yet the RNA determinants that mediate localization remain poorly understood.