Programming Human Pluripotent Stem Cells into White and Brown Adipocytes

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2012 Jan 17

PMID 22246346

Citations 131

Authors

Tim Ahfeldt

Robert T Schinzel

Youn-Kyoung Lee

David Hendrickson

Adam Kaplan

David H Lum

Raymond Camahort

Fang Xia

Jennifer Shay

Eugene P Rhee

Clary B Clish

Rahul C Deo

Tony Shen

Frank H Lau

Alicia Cowley

Greg Mowrer

Heba Al-Siddiqi

Matthias Nahrendorf

Kiran Musunuru

Robert E Gerszten

John L Rinn

Chad A Cowan

Affiliations

Soon will be listed here.

Abstract

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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References

Rhee E, Souza A, Farrell L, Pollak M, Lewis G, Steele D . Metabolite profiling identifies markers of uremia. J Am Soc Nephrol. 2010; 21(6):1041-1051. PMC: 2900954. DOI: 10.1681/ASN.2009111132. View

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

Farmer S . Transcriptional control of adipocyte formation. Cell Metab. 2006; 4(4):263-73. PMC: 1958996. DOI: 10.1016/j.cmet.2006.07.001. View

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

Tashiro K, Kawabata K, Sakurai H, Kurachi S, Sakurai F, Yamanishi K . Efficient adenovirus vector-mediated PPAR gamma gene transfer into mouse embryoid bodies promotes adipocyte differentiation. J Gene Med. 2008; 10(5):498-507. DOI: 10.1002/jgm.1171. View

Lee G, Papapetrou E, Kim H, Chambers S, Tomishima M, Fasano C . Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature. 2009; 461(7262):402-6. PMC: 2784695. DOI: 10.1038/nature08320. View

Cannon B, Nedergaard J . Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84(1):277-359. DOI: 10.1152/physrev.00015.2003. View

Tontonoz P, Hu E, Spiegelman B . Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994; 79(7):1147-56. DOI: 10.1016/0092-8674(94)90006-x. View

Xiong C, Xie C, Zhang L, Zhang J, Xu K, Fu M . Derivation of adipocytes from human embryonic stem cells. Stem Cells Dev. 2006; 14(6):671-5. DOI: 10.1089/scd.2005.14.671. View

10.

Al Yacoub N, Romanowska M, Haritonova N, Foerster J . Optimized production and concentration of lentiviral vectors containing large inserts. J Gene Med. 2007; 9(7):579-84. DOI: 10.1002/jgm.1052. View

11.

Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S . PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008; 454(7207):961-7. PMC: 2583329. DOI: 10.1038/nature07182. View

12.

Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J . High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009; 58(7):1526-31. PMC: 2699872. DOI: 10.2337/db09-0530. View

13.

van Harmelen V, Astrom G, Stromberg A, Sjolin E, Dicker A, Hovatta O . Differential lipolytic regulation in human embryonic stem cell-derived adipocytes. Obesity (Silver Spring). 2007; 15(4):846-52. DOI: 10.1038/oby.2007.595. View

14.

de Jesus L, Carvalho S, Ribeiro M, Schneider M, Kim S, Harney J . The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest. 2001; 108(9):1379-85. PMC: 209445. DOI: 10.1172/JCI13803. View

15.

Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

16.

Bermingham Jr J, Shumas S, Whisenhunt T, Sirkowski E, OConnell S, Scherer S . Identification of genes that are downregulated in the absence of the POU domain transcription factor pou3f1 (Oct-6, Tst-1, SCIP) in sciatic nerve. J Neurosci. 2002; 22(23):10217-31. PMC: 6758772. View

17.

Zuk P, Zhu M, Mizuno H, Huang J, Futrell J, Katz A . Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001; 7(2):211-28. DOI: 10.1089/107632701300062859. View

18.

Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K . Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2008; 1(1):55-70. DOI: 10.1016/j.stem.2007.05.014. View

19.

Tiscornia G, Singer O, Verma I . Production and purification of lentiviral vectors. Nat Protoc. 2007; 1(1):241-5. DOI: 10.1038/nprot.2006.37. View

20.

Stadtfeld M, Brennand K, Hochedlinger K . Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol. 2008; 18(12):890-4. PMC: 2819222. DOI: 10.1016/j.cub.2008.05.010. View