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Lau, Frank

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Lau

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Frank

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Lau, Frank
Author's Publications: search.filters.isAuthorOfPublication.7d7f49e6-dff8-4042-a134-a9ed4f5a4163

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    Generation of Multipotent Lung and Airway Progenitors from Mouse ESCs and Patient-Specific Cystic Fibrosis iPSCs
    (Elsevier BV, 2012) Mou, Hongmei; Zhao, Rui; Sherwood, Richard; Ahfeldt, Tim; Lapey, Allen; Wain, John Charles; Sicilian, Leonard; Izvolsky, Konstantin; Lau, Frank; Musunuru, Kiran; Cowan, Chad; Rajagopal, Jayaraj
    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.
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    Programming human pluripotent stem cells into white and brown adipocytes
    (Nature Publishing Group, 2012) Ahfeldt, Tim; Schinzel, Robert T.; Lee, Youn-Kyoung; Hendrickson, David Gillis; Kaplan, Adam; Lum, David H.; Camahort, Raymond; Xia, Fang; Shay, Jennifer B.; Rhee, Eugene; Clish, Clary B.; Deo, Rahul C.; Shen, Tony; Lau, Frank; Cowley, Alicia; Mowrer, Greg; Al-Siddiqi, Heba; Nahrendorf, Matthias; Musunuru, Kiran; Gerszten, Robert; Rinn, John; Cowan, Chad
    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.
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    Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA
    (Elsevier BV, 2010) Warren, Luigi; Manos, Philip D.; Ahfeldt, Tim; Loh, Yuin-Han; Li, Hualin; Lau, Frank; Ebina, Wataru; Mandal, Pankaj; Smith, Zachary; Meissner, Alexander; Daley, George; Brack, Andrew S; Collins, James; Cowan, Chad; Schlaeger, Thorsten; Rossi, Derrick
    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.
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    Expression Analysis of Macrodactyly Identifies Pleiotrophin Upregulation
    (Public Library of Science, 2012) Lau, Frank; Xia, Fang; Kaplan, Adam; Cerrato, Felecia; Greene, Arin; Taghinia, Amir; Cowan, Chad; Labow, Brian
    Macrodactyly is a rare family of congenital disorders characterized by the diffuse enlargement of 1 or more digits. Multiple tissue types within the affected digits are involved, but skeletal patterning and gross morphological features are preserved. Not all tissues are equally involved and there is marked heterogeneity with respect to clinical phenotype. The molecular mechanisms responsible for these growth disturbances offer unique insight into normal limb growth and development, in general. To date, no genes or loci have been implicated in the development of macrodactyly. In this study, we performed the first transcriptional profiling of macrodactyly tissue. We found that pleiotrophin (PTN) was significantly overexpressed across all our macrodactyly samples. The mitogenic functions of PTN correlate closely with the clinical characteristics of macrodactyly. PTN thus represents a promising target for further investigation into the etiology of overgrowth phenotypes.