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WO1996032961A1 - Compositions et procedes de regulation de la croissance des cheveux - Google Patents

Compositions et procedes de regulation de la croissance des cheveux Download PDF

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Publication number
WO1996032961A1
WO1996032961A1 PCT/US1996/005492 US9605492W WO9632961A1 WO 1996032961 A1 WO1996032961 A1 WO 1996032961A1 US 9605492 W US9605492 W US 9605492W WO 9632961 A1 WO9632961 A1 WO 9632961A1
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Prior art keywords
cells
growth
hair
follicular
modulating
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PCT/US1996/005492
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English (en)
Inventor
Robert M. Lavker
Tung-Tien Sun
Da-Wen Yu
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New York University NYU
University of Pennsylvania Penn
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New York University NYU
University of Pennsylvania Penn
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Priority to MX9708045A priority Critical patent/MX9708045A/es
Priority to EP96912950A priority patent/EP0821592A4/fr
Priority to JP8531963A priority patent/JPH11504016A/ja
Priority to CA002216870A priority patent/CA2216870C/fr
Publication of WO1996032961A1 publication Critical patent/WO1996032961A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0625—Epidermal cells, skin cells; Cells of the oral mucosa
    • C12N5/0627—Hair cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/998—Proteins not provided for elsewhere

Definitions

  • This invention relates to compositions and methods for regulating hair growth.
  • This application is a continuation-in- part of U.S. Application Serial No. 08/086,199 filed July 1, 1993; which is a continuation-in-part of U.S. Serial No. 07/ 971,687, filed November 4, 1992, which was issued as U.S. Patent 5,279,960 on January 18, 1994; which was a continuation of U.S. Application Serial No. 07/676,185, filed March 27, 1991, now abandoned.
  • This invention was made in the course of research supported by the National Institutes of Health. The U.S. Government may have certain rights in this invention.
  • Stem cells are by definition present in all self-renewing tissues. These cells are believed to be long-lived, have a great potential for cell division and are ultimately responsible for the homeostasis of steady-state tissues. Stem cells rarely incorporate radioisotopes after single pulse labeling indicating that they are normally slow-cycling. They can, however, be induced to enter the proliferative pool in response to certain growth stimuli. When stem cells undergo occasional cell division, they give rise to more rapidly proliferating "transient amplifying cells” (“TA”) which incorporate a radiolabel such as tritiated thymidine ( 3 H-TdR) after a single exposure.
  • TA transient amplifying cells
  • Stem cells possess many of the following properties: they are relatively undifferentiated, ultrastructurally and biochemically; they have a large proliferative potential and are responsible for the long term maintenance and regeneration of the tissue; they are normally "slow-cycling", presumably to conserve their proliferative potential and to minimize DNA errors that could occur during replication; they can be stimulated to proliferate in response to wounding and to certain growth stimuli; they are often located in close proximity to a population of rapidly proliferating cells corresponding to the transient amplifying cells ("TA") in the scheme of (1) stem cell to (2) TA cell to (3) terminally differentiated cell, and they are usually found in well protected, highly vascularized and innervated areas.
  • TA transient amplifying cells
  • Cotsarelis et al . , J. Invest . Dermol . 1989a, 92(3) disclose a method to facilitate detection of LRCs based on the ability of slow-cycling cells to be recruited to proliferate in response to hyperplastic stimuli.
  • AlzetTM osmotic minipumps were intraperitoneally implanted in adult SENCAR mice to deliver 20 ⁇ Ci of tritiated thymidine ( H-TdR) per day for 14 days.
  • H-TdR tritiated thymidine
  • 0.01% O- tetradecanoylphorbol 13-acetate (TPA) in petroleum (Pet) was applied topically once daily for 4 days to the right flank. The contralateral side was treated with Pet only.
  • TPA- and Pet- treated skin was examined by light microscopy and tissue section autoradiography. It was found that TPA treatment caused marked epidermal and follicular hyperplasia, whereas Pet-treated sites did not appear morphologically altered.
  • Fourteen days of continuous 3 H-TdR resulted in greater than 90% labeling of all nucleated epidermal and follicular epithelial cells in both TPA- and Pet-treated sites. After 4 weeks, only a small number of cells remained labeled (LRCs) . These cells were detected with greater frequency in TPA than Pet-treated epidermis. The most striking concentration of LRCs was found to occur in the follicular epithelium.
  • tritiated thymidine ( 3 H-TdR) labeling a subpopulation of corneal epithelial basal cells located in the peripheral cornea in a region called the limbus, were identified by Cotsarelis et al . , in Cell 1989b, 57:201-209. These cells are normally slow-cycling but can be stimulated to proliferate in response to wounding and to administration of TPA.
  • the corneal epithelium appears to represent an exceptional situation. LRCs were detected in the basal layer of limbal epithelium. No such cells were detected in central corneal epithelium.
  • limbal epithelium can be selectively stimulated to proliferate by introducing a wound 1- 2 mm away in the central corneal epithelium. Preferential stimulation of limbal epithelial proliferation was also observed when TPA was topically applied to the anterior surface of the eye. It was, therefore, concluded that the limbal epithelium has a greater proliferative potential than central corneal epithelium.
  • corneal epithelial cells as well as the stem cells of a number of other epithelia including palmar (palm) epithelium, trunk epidermis, hair follicle, dorsal tongue epithelium, and intestinal epithelium are discussed.
  • palmar (palm) epithelium the predominant epithelia
  • trunk epidermis the predominant epithelia
  • hair follicle the predominant epithelia
  • dorsal tongue epithelium a number of other epithelia
  • intestinal epithelium are discussed.
  • Figure 7(e) it is shown that in hair follicles, the heavily pigmented stem cells are located at the base, in close proximity with follicular papillae and associated vasculature.
  • Follicular papilla cells have been shown to play an important role in "activating" the normally slow-cycling follicular epithelial stem cells to proliferate resulting in the initiation of anagen (the growing phase of the hair cycle; Cotsarelis et al . , 1990 supra) .
  • the molecular mechanism by which the follicular papilla cells actually signal the epithelial stem cells to divide is, however, obscure.
  • nexin I is present in great abundance in the papillae of both vibrissa and pelage hair follicles. Moreover, its level changes significantly during different phases of the hair cycle, peaking during anagen phase VI.
  • Several established rat follicular papilla cell lines showed a broad range of nexin I mRNA levels which were found to correlate with each cell line's ability to support follicular epithelial cells to reconstitute follicles in athymic mice.
  • the identification of nexin I as a major component of the papillae of growing, but not resting, hair follicles indicates that nexin I or analogues thereof can have a major role in follicular regulation and hair growth.
  • Another dermal papilla cell cDNA has been found to encode osteopontin.
  • the inventors located the putative stem cells of the hair follicle, and possibly the sebaceous gland and epidermis, to the bulge region of the hair follicle. Using autoradiographic techniques designed to detect slow-cycling cells (label- retaining cells; LRCs) , it found, unexpectedly, that there were very few LRCs in the epidermis. Furthermore, when the hair follicle was surveyed, the inventors determined that there were no LRCs in the matrix cells comprising the bulb, which is the region that was thought to contain all of the follicle stem cells. Rather, the inventors determined that there was a subpopulation of LRCs in the upper portion of the follicle in a region known as the "bulge".
  • the bulge cells possess many stem cell properties. They mark the end of the permanent portion of the hair follicle. They possess a relatively primitive cytoplasm. They are normally slow-cycling, but can be stimulated to proliferate by tumor promoter, TPA. Finally, they are located in a physically well protected and well nourished area. The inventors' identification of a population of putative stem cells located exclusively in the vicinity of the bulge area is consistent with their being the long-hypothesized pluripotent stem cells, giving rise not only to the hair follicle, but also the sebaceous gland and epidermis.
  • the bulge is a subpopulation of outer root sheath cells located in the midportion of the follicle at the arrector pili muscle attachment site.
  • the prior art taught that hair follicle stem cells reside in the matrix or lower bulb area of the hair bulb.
  • the inventors' discovery provided insight into hair cycle control and the involvement of hair follicle stem cells in skin carcinogenesis and led to the development of methods for identifying and modulating the activity of slow- cycling cells for diagnostic and therapeutic purposes and for evaluating the efficacy of agents for modulating the activity of identified stem cell populations.
  • One of the most distinguishing features of stem cells is their slow-cycling nature.
  • a single pulse of a radioisotope such as 3 H-TdR will not label stem cells; labeling requires repeated administration of the isotope for a prolonged period of time. Once labeled, cells that cycle slowly retain isotopes for an extended period of time.
  • a discrete population of mouse hair follicle cells has been identified. These cells are slow-cycling but can be induced into the proliferative phase in response to hyperproliterative stimuli. The location of these cells was unexpected.
  • the stem cells were not found in the matrix area of the bulb where follicular stem cells are currently thought to reside. Rather, the cells were identified in a specific area of the outer root sheath, the bulge.
  • the bulge structure is not unique to the hair follicles of the mouse.
  • Outer root sheath bulges are also found in human hair follicles, as well as trunk and neck skin.
  • the bulge area has attracted so little attention by prior art workers that it is rarely even mentioned in histology text books.
  • the realization that hair follicle stem cells may reside in the bulge area has provided new insights to the inventors into how the hair cycle is regulated and the involvement of hair follicles in skin carcinogeneses .
  • the bulge stem cells are activated by dermal papillae during late telogen. This is termed "bulge activation" .
  • the dermal papillae are activated by the matrix during mid-anagen.
  • Matrix cells are in fact, TA cells; therefore, contrary to the teachings of the prior art, matrix cells have a limited proliferative potential.
  • the upward movement of dermal papillae is important for the activation of hair stem cells. Defects in any of these elements can result in abnormal hair growth or hair loss.
  • cytokines such as Tumor Necrosis Factor (TNF) , Epidermal Growth Factor (EGF) , Transforming Growth Factor (TGF) and Interleukin-1 (IL-1) are believed to be useful.
  • TNF Tumor Necrosis Factor
  • EGF Epidermal Growth Factor
  • TGF Transforming Growth Factor
  • IL-1 Interleukin-1
  • EGF cytokines
  • TNF cytokines
  • EGF- ⁇ has been shown to be involved in the regulation of both growth and differentiation of epithelial cells. It is known to stimulate keratinocyte growth in vi tro.
  • IL-1 is known to induce proliferative activity in epidermal cells.
  • cytokines are added to explants of murine skin. Explant cultures are serially harvested at daily intervals for the first 4 days of exposure, and cytokine effects on 3 H-TdR incorporation assessed in accordance with standard techniques.
  • mice In another series of experiments, a cohort of mice is continuously labeled for 2 weeks with 3 H-TdR and then allowed to rest for 4 weeks. Once labeled, cells which cycle slowly retain the isotope for an extended period of time and are, thus, identified as label retaining cells. Cytokines are introduced via intradermal injection to continuously labeled/chased animals. Four hours prior to sacrifice, colcemide (4 mg/kg) is injected intraperitoneally. Animals are sacrificed at 2, 6, 12 and 24 hours after cytokine injection and skin from injected areas fixed and processed for autoradiography according to routine procedures. Appearance of labeled mitotic figures indicates that slow cycling cells have been induced to proliferate.
  • RNAs have now been identified which encode growth modulating molecules which are synthesized by follicular cells (but not by other neighboring cells) and which undergo hair-cycle-dependent concentration changes in the hair follicle.
  • nexin I message is present in large amounts in anagen follicles almost exclusively in the papillae.
  • Nexin I message was also detected in telogen follicles; not in the papillae, but rather in keratinocytes of the lower portion of the follicle.
  • Levels of nexin I message in several established rat follicular papillary cell lines correlated well with the cell line's ability to support follicular growth in an in vivo reconstitution assay.
  • Nexin I also known as glia-derived nexin I, is a 43- to 47-kD protein. It is a potent serine-protease inhibitor. It inactivates its target proteases by forming a 1:1 covalent complex releasing in this process its own C-terminal peptide. Its target enzymes include thrombin, urokinase and tissue plasminogen activator. It has been shown to play important roles in regulating cellular growth and differentiation.
  • Nexin I or analogues thereof have been proposed for use in a number of different conditions.
  • U.S. Patent 5,206,017 and U.S. patent 5,326,562 disclose use of pharmaceutical compositions containing nexin I in the treatment of inflammation and more specifically arthritis.
  • U.S. Patent 5,187,089 also discloses use of nexin I analogues in the treatment of inflammation; in addition, this patent discloses use of nexin I analogues in the treatment of emphysema, congenital- ⁇ -1-antitrypsin deficiency, cancer, septic shock, stroke and heart attack.
  • U.S. Patents 5,112,608 and 5,196,196 disclose the use of nexin I in the promotion of wound healing.
  • U.S. Patent 5,134,076 discloses the use of nexin I in neurological disorders and WO 9105566 discloses the use of nexin I as an anticoagulant.
  • Osteopontin message was also found in cultured follicular dermal papilla cells, but not in cultured fibroblasts. Osteopontin is known to be a major bone matrix protein; however, its presence in follicles was not previously known. Osteopontin is also a secreted protein which may be involved in the regulation of follicular epithelial growth and hair growth.
  • cDNAs of rat follicular papilla cells and skin fibroblasts that have been cultured under identical in vi tro conditions were generated and compared by polyacrylamide gel electrophoresis.
  • Fourteen 5'-upstream random primers coupled with twelve 3' -downstream NM-oligo(dT) 12 primers were used to perform a total of 168 polymerase chain reactions. Each reaction gave rise to an average of about 25 cDNA bands that could be adequately resolved using a 6% polyacrylamide gel.
  • the follicular papillary and dermal fibroblastic cDNAs generated were similar except for a cDNA doublet of 210-bp and 190-bp that was present in much larger quantities in dermal papilla cells than in fibroblasts.
  • the amplification of the upper 210-bp band frequently led to the formation of the same 210-bp/190-bp doublet, indicating that these two bands were closely related.
  • the 210-bp cDNA was cloned and designated FP- 8.
  • Northern blot analysis confirmed that this mRNA species, about 1.3-Kb in size, was present as a major component accounting for >3% of the total mRNA in cultured follicular papillary cells.
  • nexin I mRNA was present in large quantities in cultured vibrissa papillary cells.
  • in situ hybridization was performed on paraffin sections of rat lip skin. The results indicated that nexin I mRNA was indeed present in abundance in vivo in the papillae of vibrissa.
  • Cells of the "connective tissue sheath" which was contiguous to and thought to be able to generate a papilla, were devoid of nexin I message. No signal was detected in any other skin mesenchymal cells, including dermal fibroblasts, adipocytes, endothelial or muscle cells.
  • telogen phase
  • the pelage follicles traverse through the hair cycle synchronously.
  • Large amounts of nexin I were detected in the papillae of anagen pelage follicles.
  • the level of nexin I mRNA greatly diminished, however, in the papillae of telogen and subsequent early anagen follicles. This suggests that the nexin I message level of follicular papillae is under stringent regulation in a hair cycle-dependent manner.
  • nexin I message Although a negligible amount of nexin I message was found in the matrix keratinocytes of anagen pelage follicles, a significant number of grains were reproducibly detected over the lower follicular keratinocytes of telogen and early anagen follicles whose papillary cells were, during these phases of the hair cycle, devoid of nexin I message.
  • nexin I message was accumulated in the papillae of anagen follicles indicated that this molecule was involved in regulating follicular growth.
  • a panel of immortalized rat vibrissa papillary cells was used to evaluate its role. It has been shown that these cell lines, when transplanted in combination with newborn mouse skin keratinocytes to athymic mice, exhibit a wide range of capacities to support the reconstitution of hair follicles.
  • Messenger RNAs from cell lines known to vary greatly in their ability to support follicular formation were isolated. PCR reactions using a specific primer pair were performed to generate cDNAs including that of nexin I. The level of nexin I mRNA varied significantly among these cell lines, and correlated well with the ability of the cell line to support follicular reconstitution.
  • nexin I message is present in large amounts in anagen follicles almost exclusively in the papillae.
  • Nexin I message was also detected in telogen follicles; however, not in papillae, but rather in keratinocytes of the lower portion of the follicle.
  • Levels of nexin I message in several established rat follicular papillary cell lines were demonstrated to correlate well with the ability of the cell line to support hair growth.
  • the follicular modulating molecule can be used to facilitate the in vi tro cultivation of follicular matrix keratinocytes.
  • Such in vi tro expanded follicular epithelial cells, in combination with appropriate papillary cells, are useful for hair reconstitution, transplantation and gene therapy.
  • growth-modulating molecules are molecules which are synthesized by follicular cells and which undergo hair-cycle dependent concentration changes in hair follicles. For example, using these methods, the inventors have already identified a cDNA in dermal papilla cells which encodes osteopontin. Using these same methods, other growth-modulating molecules can be identified.
  • compositions which comprise a growth-modulating molecule which is synthesized by follicular cells and which undergoes hair-cycle-dependent concentration changes in hair follicles, preferably nexin I or an analogue thereof.
  • Methods for identifying such molecules have been clearly provided in this disclosure.
  • These compositions of the present invention are useful in modulating the growth and differentiation of selected follicular cells through confluency.
  • selected cells such as follicular epithelial cells
  • an effective amount of a selected growth-modulating molecule so that hair growth in these cells is modulated.
  • effective amount it is meant a concentration of a growth-modulating molecule which is capable of modulating hair growth.
  • compositions of the present invention are also useful for hair reconstitution or transplantation.
  • follicular epithelial cells are expanded in vi tro by contacting the follicular epithelial cells with a selected growth-modulating molecule and combining the expanded cells with selected papillary cells.
  • Compositions comprising a growth-modulating molecule can also be administered parenterally such as subcutaneously or intramuscularly or topically to modulate hair growth in vivo .
  • a growth modulating molecule such as nexin I is not applied in pure form, but is formulated in combination with one or more excipients.
  • the composition may include a excipient such as saline.
  • excipients may encompass any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such agents is known in the art. Supplemental active ingredients may also be incorporated.
  • the amount of the growth modulating molecule needed in order to modulate hair growth varies depending upon the particular individual. Further, the number of applications and the period of time over which the applications are made can vary considerably depending upon the actual state of the follicular cells.
  • compositions comprised of 0.1 to 1.0 weight percent of a growth modulating factor such as nexin I and 99.99 to 99.0 weight percent of excipient can be applied topically on a daily basis over a period of one month.
  • a growth modulating factor such as nexin I
  • 99.99 to 99.0 weight percent of excipient can be applied topically on a daily basis over a period of one month.
  • the growth modulating molecule be formulated in a semisolid cream, ointment or gel formulation.
  • the formulation may also be in the form of a solution having the growth modulating molecule therein.
  • the type of formulation and amount of the formulation applied will be determined to a large extent by the caregiver. While a single application of the growth modulating molecule may be effective, in order to obtain the best results it may be necessary to apply it periodically, such as every day, or every other day depending upon the individual and the state of the cells being treated. Again the amount of the growth modulating molecule and the frequency at which it is applied, is a matter which can readily be determined by one skilled in the art based upon visual changes observed in hair growth.
  • Vibrissa follicles were dissected individually from the lip region of young (1-2 months old) Wistar rats and their papillae squeezed out using a pair of forceps.
  • the isolated papillae were placed in a small amount of Chang's medium (1.5 ml per 60 mm) and left undisturbed in a 37°C incubator (5% C0 2 ) for 4 days. Under these conditions, most of the papillae formed outgrowth (Jahoda and Oliver, Br. J. Derm . 1981, 105:623-627; Warren et al . , J " . Invest. Derm . 1992, 98:693-9) .
  • the cells were treated with 0.1% trypsin and 0.1% EDTA in phosphate-buffered saline and the dissociated single cells were then plated in Dulbecco's Minimal Essential Medium containing 10% fetal calf serum.
  • the lip skin tissues, from which the vibrissae have been removed, were then minced thoroughly to ⁇ 1 mm 3 and placed under outgrowth conditions and subcultured as described above. Under these conditions, the papillary cells and dermal fibroblasts maintained distinct morphology (Jahoda and Oliver, 1981 supra ; Jahoda and Oliver, J. Embro . and Exper. Morph . 1984a, 79:211- 224) .
  • RNAs of the cultured cells were extracted in 4M guanidium chloride, purified by ultracentrifugation and treated with RNase-free bovine pancreatic DNase (Chomcqynski and Sacchi, Anal. Biochem . 1987, 162:156-159) .
  • RNAs of cultured cells were reverse-transcribed/PCRed using twelve 3"-oligo (dT) 12 primers (14-bp) coupled with fourteen 5' -random primers (10-bp oligodeoxynucleotides) according to Liang and Pardee, Sci ence 1992, 257:967-971.
  • PCR polymerase chain reaction
  • the cDNAs were resolved on a 6% polyacrylamide DNA sequencing gel. The area of a dried gel containing a cDNA fragment of interest was excised and extracted by heating in distilled water at 90°C for 5 minutes. The solubilized partial cDNA was used as the template for two rounds of reamplification using the original pair of primers.
  • the fragment was cloned into a PCRII vector and sequenced using the dideoxynucleotide procedure of Singer (US Biochemical Kit) .
  • Northern blot analysis and in si tu hybridization were performed according to previously described procedures.
  • Example 3 In vivo screening of growth-modulating molecules
  • a full-length cDNA for the growth-modulating molecule is generated by PCR using standard techniques. After cDNA cloning, a recombinant growth-modulating molecule is generated in bacteria and subsequently administered to mice to determine whether the growth-modulating molecule prolongs the anagen of the mouse hair cycle. Administration to the mouse is performed either by implanting subcutaneously heparin acrylic beads soaked in the growth-modulating molecule to be screened or by implanting a slow-releasing micro-pump which release the molecule slowly over a prolonged period.
  • the hair cycle in mice is well characterized with newborn animals having relatively primitive follicles which develop postnatally maturing around day 19 to 21 after which they enter abruptly into a catagen and a brief telogen.
  • the second cycle begins around day 25 lasting about 10 days before entering into a prolonged telogen of approximately 20 days. Initially, it is determined whether in vivo administration of the growth- modulating molecule prolongs the second anagen. In addition, using this model it can be determined whether the growth- modulating molecule, in comparison to control proteins such as albumin, induces the premature onset and prolongation of the third anagen, which normally occur around day 45.

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Abstract

L'invention se rapporte à un procédé de modulation de la croissance des cheveux, consistant à mettre en contact des cellules sélectionnées avec une molécule sélectionnée modulatrice de la croissance des cheveux. L'invention se rapporte également à un procédé de reconstitution ou de transplantation des cheveux par dilatation in vitro des cellules sélectionnées et par leur association à d'autres cellules qui régulent la croissance des cheveux. L'invention se rapporte en outre à des compositions contenant une molécule modulatrice de la croissance des cheveux qui est synthétisée par des cellules folliculaires et qui subit des variations de concentration dans les follicules pileux en fonction du cycle pilaire.
PCT/US1996/005492 1995-04-20 1996-04-19 Compositions et procedes de regulation de la croissance des cheveux Ceased WO1996032961A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
MX9708045A MX9708045A (es) 1995-04-20 1996-04-19 Composiciones y metodos para regular el crecimiento del cabello.
EP96912950A EP0821592A4 (fr) 1995-04-20 1996-04-19 Compositions et procedes de regulation de la croissance des cheveux
JP8531963A JPH11504016A (ja) 1995-04-20 1996-04-19 毛髪の成長を調節する組成物及び方法
CA002216870A CA2216870C (fr) 1995-04-20 1996-04-19 Compositions et procedes de regulation de la croissance des cheveux

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US42578695A 1995-04-20 1995-04-20
US08/425,786 1995-04-20

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Cited By (3)

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NL1005445C2 (nl) * 1997-03-05 1998-09-21 Gho St Holding B V Werkwijze voor het vermenigvuldigen van haar.
WO2013021212A3 (fr) * 2011-08-10 2014-04-17 Follicum Ab Nouvelles compositions et leurs utilisations
US20220380734A1 (en) * 2019-09-26 2022-12-01 Duke University Systems and methods for lung cell expansion and differentiation

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NL1005445C2 (nl) * 1997-03-05 1998-09-21 Gho St Holding B V Werkwijze voor het vermenigvuldigen van haar.
WO1998047471A1 (fr) * 1997-03-05 1998-10-29 Gho'st Holding B.V. Procede de reproduction des cheveux
AU732729B2 (en) * 1997-03-05 2001-04-26 Gho Holding B.V. Method for the propagation of hair
US6399057B1 (en) 1997-03-05 2002-06-04 Gho'st Holding B. V. Method for the propagation of hair
WO2013021212A3 (fr) * 2011-08-10 2014-04-17 Follicum Ab Nouvelles compositions et leurs utilisations
CN103930125A (zh) * 2011-08-10 2014-07-16 富力卡姆股份公司 具有失活rgd域的修饰的骨桥蛋白肽及其用途
US9381149B2 (en) 2011-08-10 2016-07-05 Folicum, Ab Compositions and uses thereof
EP3087999A1 (fr) * 2011-08-10 2016-11-02 Follicum AB Ostéopontine modifiée ayant un domaine rgd inactivé et utilisations
RU2604797C2 (ru) * 2011-08-10 2016-12-10 Фолликум Аб Новые композиции и их применение
US10137169B2 (en) 2011-08-10 2018-11-27 Follicum Ab Compositions and uses thereof
US10517932B2 (en) 2011-08-10 2019-12-31 Follicum Ab Compositions and uses thereof
US20220380734A1 (en) * 2019-09-26 2022-12-01 Duke University Systems and methods for lung cell expansion and differentiation

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MX9708045A (es) 1998-03-31
CA2216870A1 (fr) 1996-10-24
CA2216870C (fr) 2002-11-19
EP0821592A1 (fr) 1998-02-04
JPH11504016A (ja) 1999-04-06
EP0821592A4 (fr) 2000-03-01

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