Frank H. Lau

Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.

Clinical application of induced pluripotent stem cells (iPSCs) is limited by the low efficiency of iPSC derivation and the fact that most protocols modify the genome to effect cellular reprogramming. Moreover, safe and effective means of directing the fate of patient-specific iPSCs toward clinically useful cell types are lacking. Here we describe a simple, nonintegrating strategy for reprogramming cell fate based on administration of synthetic mRNA modified to overcome innate antiviral responses. We show that this approach can reprogram multiple human cell types to pluripotency with efficiencies that greatly surpass established protocols. We further show that the same technology can be used to efficiently direct the differentiation of RNA-induced pluripotent stem cells (RiPSCs) into terminally differentiated myogenic cells. This technology represents a safe, efficient strategy for somatic cell reprogramming and directing cell fate that has broad applicability for basic research, disease modeling, and regenerative medicine.

Generation of Multipotent Lung and Airway Progenitors from Mouse ESCs and Patient-Specific Cystic Fibrosis iPSCs

Deriving lung progenitors from patient-specific pluripotent cells is a key step in producing differentiated lung epithelium for disease modeling and transplantation. By mimicking the signaling events that occur during mouse lung development, we generated murine lung progenitors in a series of discrete steps. Definitive endoderm derived from mouse embryonic stem cells (ESCs) was converted into foregut endoderm, then into replicating Nkx2.1+ lung endoderm, and finally into multipotent embryonic lung progenitor and airway progenitor cells. We demonstrated that precisely-timed BMP, FGF, and WNT signaling are required for NKX2.1 induction. Mouse ESC-derived Nkx2.1+ progenitor cells formed respiratory epithelium (tracheospheres) when transplanted subcutaneously into mice. We then adapted this strategy to produce disease-specific lung progenitor cells from human Cystic Fibrosis induced pluripotent stem cells (iPSCs), creating a platform for dissecting human lung disease. These disease-specific human lung progenitors formed respiratory epithelium when subcutaneously engrafted into immunodeficient mice.

Programming human pluripotent stem cells into white and brown adipocytes

The utility of human pluripotent stem cells is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into white or brown adipocytes. We found that inducible expression of PPARG2 alone or combined with CEBPB and/or PRDM16 in mesenchymal progenitor cells derived from pluripotent stem cells programmed their development towards a white or brown adipocyte cell fate with efficiencies of 85%–90%. These adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers and had mature functional properties such as lipid catabolism and insulin-responsiveness. When transplanted into mice, the programmed cells gave rise to ectopic fat pads with the morphological and functional characteristics of white or brown adipose tissue. These results indicate that the cells could be used to faithfully model human disease.

A cost/utility analysis of open reduction and internal fixation versus cast immobilization for acute nondisplaced mid-waist scaphoid fractures.

Background: Open reduction and internal fixation and cast immobilization are both acceptable treatment options for nondisplaced waist fractures of the scaphoid. The authors conducted a cost/utility analysis to weigh open reduction and internal fixation against cast immobilization in the treatment of acute nondisplaced mid-waist scaphoid fractures. Methods: The authors used a decision-analytic model to calculate the outcomes and costs of open reduction and internal fixation and cast immobilization, assuming the societal perspective. Utilities were assessed from 50 randomly selected medical students using the time trade-off method. Outcome probabilities taken from the literature were factored into the calculation of quality-adjusted life-years associated with each treatment. The authors estimated medical costs using Medicare reimbursement rates, and costs of lost productivity were estimated by average wages obtained from the U.S. Bureau of Labor Statistics. Results: Open reduction and internal fixation offers greater quality-adjusted life-years compared with casting, with an increase ranging from 0.21 quality-adjusted life-years for the 25- to 34-year age group to 0.04 quality-adjusted life-years for the ≥65-year age group. Open reduction and internal fixation is less costly than casting (

Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities

7940 versus

Efficient culturing and genetic manipulation of human pluripotent stem cells.

13,851 per patient) because of a longer period of lost productivity with casting. Open reduction and internal fixation is therefore the dominant strategy. When considering only direct costs, the incremental cost/utility ratio for open reduction and internal fixation ranges from

The New Accreditation Council for Graduate Medical Education Next Accreditation System Milestones Evaluation System: What Is Expected and How Are Plastic Surgery Residency Programs Preparing?

5438 per quality-adjusted life-year for the 25- to 34-year age group to

Induced pluripotent stem (iPS) cells: an up-to-the-minute review

11,420 for the 55- to 64-year age group, and

Wound healing in acutely injured fascia

29,850 for the ≥65-year age group. Conclusions: Compared with casting, open reduction and internal fixation is cost saving from the societal perspective (

Expression analysis of macrodactyly identifies pleiotrophin upregulation.

5911 less per patient). When considering only direct costs, open reduction and internal fixation is cost-effective relative to other widely accepted interventions.