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Topical selective delivery of liposome-lacZ gene to hair follicle of mice

Lingna Li and Robert M. Hoffman: The feasibility of targeted selective gene therapy of the hair follicle. Nature Medicine, 1, 705-706, 1995

_{Blue color indicates lac-Z gene expression in the matrix cells of hair follicle bulb, magnification: a)  400X, b) 1000X} 

Hair shafts genetically modified with GFP growing in mice

SOURCE: Proceedings of the National Academy of Sciences 2002;10.1073/pnas.192453799./Saito, N., Zhao, M., Li.L., Baranov, E., Yang, M., Ohta, Y., Katsuoka, K., Penman, S., and Hoffman R.M. High efficiency genetic modification of hair follicles and growing hair shafts. Proc. Natl. Acad. Sci USA  99, 1310-1314, 2002.

_{IN VITRO HISTOCLTURE HAIR GROWTH ASSAY}

Hair growth with progressing pigment production from anagen-induced C57 Bl-6 mouse skin 

_{Lingna Li et al. Skin histoculture assay for studying the hair cycle. In Vitro Cell. Dev. Biol., 28A:695-698, 1992}

_{Lingna Li et al. Hair shaft elongation, follicle growth, and spontaneous regression in long-term, gelatin sponge-supported histoculture of human scalp skin. Proc. Natl. Acad. Sci. USA Vol. 89, pp.8764-8768, 1992}

SCREEN FOR: Hair Growth Stimulators and Inhibitors, Inhibitors of Chemotherpay Induced Alopecia, Hair Pigment Modifier, Acne Inhibitors - CUSTOMIZED CONTRACT RESEARCH AVAILABLE AT ANTICANCER INC.

Hair-brain connection: Expression of neural stem cell marker nestin found in hair follicle stem cells. 

Li, L., Mignone, J., Yang. M., Matic, M., Penman, S., Enikolopov, G. Nestin Expression in hair follicle sheath progenitor cells. Proc. Natl. Acad. Sci. USA 100(17), 9958-9961, 2003. [PDF]

Transgenic mice with nestin-driven green fluorescent protein (GFP) were found to have nestin expressed in hair follicle stem cells and the developing hair follicle. 

Fig. 1 Nestin-GFP expression in hair follicle stem cells during hair cycle

Nestin-expressing hair follicle stem cells visualized forming the hair follicle by GFP fluorescence.

Fig. 2 Nestin-GFP-expressing stem cells in telogen hair follicle

a1: Low magnification (100X) fluorescence microscopy image shows the ring of bulge nestin-GFP-expressing stem cells (small white box)

a2: High magnification (400X) confocal microscopy image shows ring of nestin-GFP-expressing stem cells in telogen hair follicle similar to that shown in a1 (large white box) 

a3: Higher magnification (1600X) fluorescence microscopy image shows two individual nestin-GFP-expressing stem cells in telogen hair follicle similar to those shown in (a2) (red box). Red arrows indicate the cell body and red arrowheads show the multiple dendritic structure of each cell. 

Fig. 3 Nestin-GFP expressing stem cells forming nascent hair follicle.

Fig. 4A. Co-localization of GFP, nestin and keratin 5/8 & 15 in hair follicle bulge stem cells and outer root sheath cells determined by immunohistochemical staining.

a: Confocal image of nestin expressing hair follicle stem cells (red arrows) forming nascent anagen hair follicle (white arrow). 
b-g: Immunohistochemical stained sections of hair follicles:
                b: Nestin antibody (red arrow) indicating expression in hair follicle stem cells and nascent hair follicle (white arrow)
                c, d: GFP antibody indicating GFP expression in hair follicle stem cells (red stain). Keratin antibody indicating keratin expression 

                        in hair follicle stem cells (brown     stain). Black arrows indicate co-localization keratin and GFP.
                e-g: Serial sections of hair follicle (green arrows indicate GFP expression; red arrows indicate keratin 5/8 expression and blue arrows indicate nestin expression) 

Fig. 4B Colocalization of nestin-GFP and keratin-15 in telogen hair follicle stem cells. 

a: Fluorescence microscopy of frozen section of bulge area of telogen hair follicle of nestin-GFP transgenic mouse counterstained with PI (propidium iodide). Note the nestin-GFP expressing hair follicle stem cells are marked with white arrows.  Magnification 400X.

b: Serial section of (a) was immunohistochemical stained with Keratin-15 mAb. Note the expression of keratin-15 (brown stain, green arrows) is colocalized with nestin-GFP in (a). Hemotoxylin counterstaining. Light microscopy. Magnification 400x. 

Targetted Expression of GFP in the Hair Follicle Using Ex Vivo Viral Transduction  (video)

DERMATEK^® PATENTS

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Australia 731,559  Canada 2159626  Europe 573,606  Europe 692,972  Japan 2,950,519  Japan 2,950,520

   DERMATEK^® BIBLIOGRAPHY

1.        Hoffman, R.M., Margolis, L.B., and Bergelson, L.D.  Binding and entrapment of high molecular weight DNA by lecithin liposomes.  Elsevier/North-Holland Biomedical Press, FEBS Letters 93, 365-368, 1978. [PDF]

2.        Li, L., Margolis, L.B., and Hoffman, R.M.  Native-state sponge-gel histoculture of intact 3-dimensional tissue for in vitro toxicity assays.  8th International CAAT Symposium, (ed.) Alan M. Goldberg, The Johns Hopkins University.  Alternative Methods in Toxicology 8, 311-316, 1991. [PDF]

3.        Li, L., and Hoffman, R.M.  Hair growth and hair follicle proliferation in histocultured mouse skin.  Annals of the New York Academy of Sciences, The Molecular and Structural Biology of Hair 642, 506-509, 1991. [PDF]

4.        Li, L., Margolis, L.B. and Hoffman, R.M.  Skin toxicity determined in vitro by three-dimensional, native-state histoculture.  Proc. Natl. Acad. Sci. USA 88, 1908-1912, 1991. [PDF]

5.        Li, L., Paus, R., Margolis, L.B., and Hoffman, R.M.  Hair growth in vitro from histocultured skin.   In Vitro Cell. Dev. Biol. 28A, 479-481, 1992. [PDF]

6.        Li, L., Paus, R., Margolis, L.B., and Hoffman, R.M.  Hair shaft elongation, follicle growth, and spontaneous regression in long-term, gelatin sponge-supported histoculture of human scalp skin.  Proc. Natl. Acad. Sci. USA 89, 8764-8768, 1992. [PDF]

7.        Li, L., Paus, R., Slominski, A., and Hoffman, R.M.  Skin histoculture assay for studying the hair cycle.  In Vitro Cell. Dev. Biol. 28A, 695-698, 1992. [PDF]

8.        Li, L., Lishko, V.K., Margolis, L.B., and Hoffman, R.M.  Product-delivering liposomes specifically target hair follicles in histocultured intact skin.  In Vitro Cell. Dev. Biol. 28A, 679-681, 1992. [PDF]

9.        Li, L., Lishko, V.K., and Hoffman, R.M.  Liposomes can specifically target entrapped melanin to hair follicles in histocultured skin.  In Vitro Cell Dev. Biol. 29A, 192-194, 1993. [PDF]

10.      Li, L., Lishko, V.K., and Hoffman, R.M.  Liposome targeting of high molecular weight DNA to the hair follicles of histocultured skin: A model for gene therapy of the hair growth processes.  In Vitro Cell Dev. Biol. 29A, 258-260, 1993. [PDF]

11.      Li, L. and Hoffman, R.M.  Histoculture radiometric in vitro hair growth assay.  In Vitro Cell. Dev. Biol. 29A, 449-450, 1993. [PDF]

12.        Li, L., Lishko, V., and Hoffman, R.M.  High efficiency liposome-mediated transfection of the tyrosinase gene  to cultured cells: A model for the gene therapy of hair color restoration.  In Vitro Cell. Dev. Biol. 30A, 135-138, 1994. [PDF]

13.      Paus, R., Kreja-Papa, N., Li, L., Czarnetski, B.M., and Hoffman, R.M.  Correlation of proteolytic activities of organ cultured intact mouse skin with defined hair cycle stages.  J. Derm. Sci. 7, 202-209, 1994. [PDF]

14.      Li, L. and Hoffman, R.M.  Model of selective gene therapy of hair growth: liposome targeting of the active Lac-Z gene to hair follicles of histocultured skin.  In Vitro Cell Dev. Biol. 31A, 11-13, 1995. [PDF]

15.      Li, L. and Hoffman, R.M.  The feasibility of targeted selective gene therapy of the hair follicle.  Nature Medicine 1, 705-706, 1995. [PDF]

16.      Zhang, L., Li, L., Hofmann, G.A., and Hoffman, R.M.  Depth-targeted efficient gene delivery and expression in the skin by pulsed electric fields:  an approach to gene therapy of skin aging and other diseases.  Biochemical and Biophysical Research Communications 220, 633-636, 1996. [PDF]

17.      Li, L. and Hoffman, R.M.  Topical liposome delivery of molecules to hair follicles in mice.   J. Derm. Sci. 14, 101-108, 1997. [PDF]

18.        Zhang, L., Li, L., An, Z., Hoffman, R.M., and Hofmann, G.A.  In vivo transdermal delivery of  large molecules by pressure-mediated electroincorporation and electroporation: a novel method for drug/gene delivery. Bioelectrochemistry and Bioenergetics 42, 283-292, 1997. [PDF]

19.        Hoffman, R.M.  Topical liposome targeting of dyes, melanins, genes, and proteins selectively to hair follicles. J. Drug Targeting 5, 67-74, 1997. [PDF]

20.        Gene scientists give grey hair the brush-off.  The Sunday Times, London, 19 September 1999. [PDF]

21.        Hoffman, R.M.  The hair follicle as a gene therapy target.  Nature Biotechnology 18, 20-21, 2000. [PDF]

22.        Wadmar, M.  Wash that gray right out of your hair.  Fortune, p. 40, February 7, 2000. [PDF]

23.        Friedman, Devin.  Tech 2010, A Catalog of the Near Future; The Makeup That Changes Your Identity. The New York Times Magazine, p. 56-57, June 11, 2000. [PDF]

24.        Zhao, M., Saito, N., Li, L., Baranov, E., Kondoh, H., Mishima, Y., Sugiyama, M., Katsuoka, K., Hoffman, R.M.  A novel approach to gene therapy of albino hair in histoculture with a retroviral Streptomyces tyrosinase gene.  Pigment Cell Research 13, 345-351, 2000. [PDF]

25.      Saito, N., Zhao, M., Li.L., Baranov, E., Yang, M., Ohta, Y., Katsuoka, K., Penman, S., and Hoffman R.M. High efficiency genetic modification of hair follicles and growing hair shafts. Proc. Natl. Acad. Sci USA  99, 1310-1314, 2002. [PDF]

26.        Hoffman, R.M. Immune reactions in skin anfd hair follicle gene therapy. Molecular Therapy 7, 294-295, 2003. [PDF]

27.      Li, L., Mignone, J., Yang. M., Matic, M., Penman, S., Enikolopov, G. Nestin Expression in hair follicle sheath progenitor cells. Proc. Natl. Acad. Sci. USA 100(17), 9958-9961, 2003. [PDF]

28.        Hoffman, R.M. Gene targeting of hair follicles. In: Hair Science and Technology, ISBN 2-9600376-0-X, pp.363-372. Van Neste, D., ed. Tournai, Belgium: Skinterface, 2003. [PDF]

29.      Amoh, Y., Li, L., Yang, M., Moossa, A.R., Katsuoka, K., Penman, S., and Hoffman, R.M.  Nascent blood vessels in the skin arise from nestin-expressing hair follicle cells.  Proc. Natl. Acad. Sci. USA 101, 13291-13295, 2004 [PDF]

30.      Amoh, Y., Li, L., Yang, M., Jiang, P., Moossa, A.R., Katsuoka, K., Hoffman, R.M. Hair-follicle-derived blood vessels vascularize tumors in skin and are inhibited by doxorubicin.  Cancer Research 65, 2337-2343, 2005 [PDF]

31.      Hoffman, R.M.  Gene and stem cell therapy of the hair follicle.  In: Epidermal Cells: Methods and Protocols. Methods in Molecular Biology, Vol. 289, pp. 437-448. Turksen, K., ed.  Totowa, NJ: Humana Press, 2005. [PDF]

32.      Hoffman, R. M. The hair follicle and its stem cells as drug delivery targets. Expert Opinion Drug Delivery 3, 437-443, 2006 [PDF]

33.      Hoffman, R.M.  The potential of nestin-expressing hair follicle stem cells in regenerative medicine. Expert Opin. Biol. Ther. 7, 289-291, 2007. [PDF]