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John M. Hutson - One of the best experts on this subject based on the ideXlab platform.
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bdnf is upregulated by androgen in the Inguinal Fat Pad of immature mice and may regulate inguinoscrotal testicular descent
Pediatric Research, 2021Co-Authors: Jaya Vikraman, John M. Hutson, Gulcan Sarila, Louise Oconner, Trevelyan R MenheniottAbstract:BACKGROUND Androgens control rodent inguinoscrotal testicular descent during a "programming window" (E12-17). It is proposed that androgen masculinises the genitofemoral nerve, but the mechanism remains unknown. We investigate androgen receptor (AR)-containing target organs: Inguinal Fat Pad (IFP) and mammary bud (MB), supplied by the genitofemoral nerve, hypothesizing that neurotrophic factors may retrogradely masculinise the GFN. METHODS The IFP, MB and bulbocavernosus (BC) muscle were collected at E12.5/E17.5 from androgen receptor knockout (ARKO) mice and wild-type (WT) littermates. Immunofluorescence and gene expression (RT-qPCR; n = 8/group) for Bdnf, active (TrkB) and inactive (truncated TrkB) receptors, Cntf and Cntf receptor were performed. RESULTS In the IFP at E12.5, ARKO TrkB mRNA expression was significantly downregulated compared to WT males (p < 0.0026). By E17.5, there was increased Bdnf expression (p < 0.0233). The MB had no differences at E12.5 and had regressed in WT males by E17.5. The BC had no differences at E12.5, but at E17.5 had significant upregulation of Bdnf expression in ARKO, compared to WT males. There were no differences in CNTF or CNTF receptor expression. CONCLUSIONS Androgen alters active TrkB and Bdnf expression in the IFP. IFP Bdnf signalling may regulate "masculinisation" of the GFN sensory nerves to indirectly control inguinoscrotal testicular descent. IMPACT Androgen mediates neurotrophin release in the Inguinal Fat Pad in mice, which may facilitate normal testicular descent by masculinising the GFN by peripheral uptake of neurotrophin. This is the first study to examine the role of neurotrophins in testicular descent. This suggests novel steps in the mechanical process of normal testicular descent that may be abnormal in some children with undescended testes.
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hoxa 11 maintains cell proliferation in the mouse gubernaculum to facilitate testicular descent
Journal of Pediatric Surgery, 2013Co-Authors: George N Harisis, Alfor G Lewis, BRIDGET RAE SOUTHWELL, John M. HutsonAbstract:Abstract Introduction The gubernaculum is a structure vital for guiding testicular descent. The Homeobox gene, Hoxa-11, is involved in patterning embryonic structures and is necessary for gubernacular development, as Hoxa-11 knock-out mice exhibit abnormal gubernacula and undescended testes. We aimed to elucidate how testicular descent fails by examining cell proliferation and androgen receptor (AR) expression in Hoxa-11 KO mice gubernacula. Methods Postnatal day 2 wild type (n=6) and Hoxa-11 KO mice (n=6), were prepared for immunohistochemistry and confocal microscopy using antibodies against androgen receptor, slow skeletal myosin (My32), and Ki67, a marker of cell proliferation. Results The gubernacula of Hoxa-11 KO mice were hypocellular compared with WT. AR was present in the gubernaculum and abutting Inguinal Fat Pad in both WT and Hoxa-11 KO with no difference in expression. Slow skeletal myosin was present in a clear ‘swirl' in the growth centre of WT animals which was absent in the Hoxa-11 KO mice. Ki67, expressed in the growth centre and cremaster muscle in WT, was greatly decreased in Hoxa-11 KO. Conclusion Hoxa-11 may regulate fibroblast proliferation in the gubernaculum, as it does in human uterosacral ligaments, allowing formation of the 'growth centre' within the bulb and facilitating myogenesis and elongation to the scrotum. Polymorphisms in Hoxa-11 may contribute to the aetiology of human cryptorchidism.
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gubernaculum as icebreaker do matrix metalloproteinases in rodent gubernaculum and Inguinal Fat Pad permit testicular descent
Journal of Pediatric Surgery, 2011Co-Authors: James Churchill, Silverton Buraundi, BRIDGET RAE SOUTHWELL, John M. Hutson, Pamela J Farmer, Ruili Li, Adam BalicAbstract:Abstract Purpose Cryptorchidism is the most common male congenital abnormality. The rodent gubernaculum steers the testis from abdomen to scrotum postnatally by eversion and migration through the developing Inguinal Fat Pad (IFP). We hypothesize that extracellular matrix remodeling in/around the gubernaculum is necessary for eversion and migration and is permitted by timed IFP maturation and aimed to examine regional development and matrix metalloproteinase (MMP) content. Methods Embryonic day 19 (E19) and postnatal days 0 and 2 (P0, P2) wild-type Sprague-Dawley rats (n = 10) were prepared for histologic examination (trichrome) and immunohistochemistry (membrane-type MMP-1 [MT1-MMP], MMP2) and analyzed using light/confocal microscopy. Results At E19, IFP contained fibroblasts and immature cells in an extensive collagenous extracellular matrix. Cells in the gubernaculum base were cytoplasmic-MT1-MMP-positive (inactive). At P0, the gubernaculum had everted, and adjacent cells were membranous-MT1-MMP-positive (active). At P2, the gubernaculum was migrating through the IFP, and adjacent cells were membranous-MT1-MMP-positive. Adipocyte maturation began cranially in the IFP and proceeded in a craniocaudal gradient until more uniformly mature at P2. Conclusion The MT1-MMP-positive cells may remodel the gubernaculum for eversion and provide the collagenolysis necessary for migration, like an icebreaking ship, through the IFP, which matures to permit migration through collagen-rich tissue. Disruption of these processes may cause cryptorchidism.
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the effect of flutamide on expression of androgen and estrogen receptors in the gubernaculum and surrounding structures during testicular descent
Journal of Pediatric Surgery, 2011Co-Authors: Tamara R Nation, Silverton Buraundi, Adam Balic, Donald F Newgreen, BRIDGET RAE SOUTHWELL, John M. Hutson, Pamela J FarmerAbstract:Abstract Background/Purpose Inguinoscrotal testicular descent is controlled by androgens between embryonic days E16-19, but androgen receptor (AR) and estrogen receptor (ER) locations are unknown. We aimed to find AR, ER α , and ER β in the gubernaculum and Inguinal Fat Pad (IFP) in normal rats and after flutamide treatment. Methods Sprague-Dawley timed-mated rats were injected with flutamide (75 mg/kg body weight/5% ethanol + oil) on E16-19 or vehicle alone. Male fetuses or pups (5-10/group) were collected at E16; E19; and postnatal (P) days 0, 2, 4, 8. Sections were prepared for hematoxylin and eosin or immunohistochemistry for AR, ERα, and ERβ. Receptor labeling was quantitated as distinct nuclear labeling/100 μ m 2 in gubernaculum and IFP. Results There was minimal gubernacular AR-labeling until E19, dramatically increasing postnatally. By contrast, at E16-E19 there was significant IFP AR immunoreactivity suppressed by flutamide ( P Conclusions During the androgen sensitivity window (E16-19), the gubernaculum contains ERβ but minimal ERα or AR, while the IFP, which is supplied by the genitofemoral nerve, contains abundant AR that are flutamide-sensitive. These results suggest that the IFP could be the site of androgenic action controlling gubernacular development.
John K. Fraser - One of the best experts on this subject based on the ideXlab platform.
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autologous adipose derived regenerative cell therapy modulates development of hypertrophic scarring in a red duroc porcine model
Stem Cell Research & Therapy, 2017Co-Authors: Philippe Foubert, Diana Zafra, Mike Liu, Rohit Rajoria, Damian Gutierrez, Mayer Tenenhaus, John K. FraserAbstract:Effective prevention and treatment of hypertrophic scars (HTSs), a common consequence of deep-partial thickness injury, remain a significant clinical challenge. Previous studies from our group have shown that autologous adipose-derived regenerative cells (ADRCs) represent a promising approach to improve wound healing and, thereby, impact HTS development. The purpose of this study was to assess the influence of local delivery of ADRCs immediately following deep-partial thickness cutaneous injury on HTS development in the red Duroc (RD) porcine model. Bilateral pairs of deep-partial thickness excisional wounds (2 mm depth; 58 cm2 area) were created using an electric dermatome on RD pigs (n = 12). Autologous ADRCs were isolated from the Inguinal Fat Pad and then sprayed directly onto the wound at a dose of 0.25 × 106 viable cells/cm2. The paired contralateral wound received vehicle control. Wound healing and development of HTS were assessed over 6 months using digital imaging, quantitative measurement of skin hardness and pigmentation, and histology. Data showed that ADRC treatment led to reduced scar hyperpigmentation compared to control (p < 0.05). Using the Durometer, at 2 and 6 months post-injury, skin hardness was 10–20% lower in ADRCs-treated wounds compared to control vehicle (p < 0.05). A similar trend was observed with the skin fibrometer. ADRC treatment promoted more normal collagen organization, improvement in the number of rete ridges (p < 0.01), longer elastic fiber length (p < 0.01), and reduced hypervascularity (blood vessel density; p < 0.05). ADRC treatment was associated with modulation of IL-6 expression within the wound/scar with upregulation 2 weeks after injury (wound healing phase) and downregulation at 2 months (early scarring phase) post-treatment compared to control These findings support the potential therapeutic value of autologous ADRC administration for reduction of HTS development following deep-partial cutaneous injury.
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Autologous adipose-derived regenerative cell therapy modulates development of hypertrophic scarring in a red Duroc porcine model
BMC, 2017Co-Authors: Philippe Foubert, Diana Zafra, Mike Liu, Rohit Rajoria, Damian Gutierrez, Mayer Tenenhaus, John K. FraserAbstract:Abstract Background Effective prevention and treatment of hypertrophic scars (HTSs), a common consequence of deep-partial thickness injury, remain a significant clinical challenge. Previous studies from our group have shown that autologous adipose-derived regenerative cells (ADRCs) represent a promising approach to improve wound healing and, thereby, impact HTS development. The purpose of this study was to assess the influence of local delivery of ADRCs immediately following deep-partial thickness cutaneous injury on HTS development in the red Duroc (RD) porcine model. Methods Bilateral pairs of deep-partial thickness excisional wounds (2 mm depth; 58 cm2 area) were created using an electric dermatome on RD pigs (n = 12). Autologous ADRCs were isolated from the Inguinal Fat Pad and then sprayed directly onto the wound at a dose of 0.25 × 106 viable cells/cm2. The paired contralateral wound received vehicle control. Wound healing and development of HTS were assessed over 6 months using digital imaging, quantitative measurement of skin hardness and pigmentation, and histology. Results Data showed that ADRC treatment led to reduced scar hyperpigmentation compared to control (p
Nancy M Sherwood - One of the best experts on this subject based on the ideXlab platform.
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gonadotropin releasing hormone receptor gnrhr gene knock out normal growth and development of sensory motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice
PLOS ONE, 2017Co-Authors: Ellen R Busby, Nancy M SherwoodAbstract:Gonadotropin-releasing hormone (GnRH) is important in the control of reproduction, but its actions in non-reproductive processes are less well known. In this study we examined the effect of disrupting the GnRH receptor in mice to determine if growth, metabolism or behaviors that are not associated with reproduction were affected. To minimize the effects of other hormones such as FSH, LH and sex steroids, the neonatal-prepubertal period of 2 to 28 days of age was selected. The study shows that regardless of sex or phenotype in the Gnrhr gene knockout line, there was no significant difference in the daily development of motor control, sensory detection or spatial orientation among the wildtype, heterozygous or null mice. This included a series of behavioral tests for touch, vision, hearing, spatial orientation, locomotory behavior and muscle strength. Neither the daily body weight nor the final weight on day 28 of the kidney, liver and thymus relative to body weight varied significantly in any group. However by day 28, metabolic changes in the GnRH null females compared with wildtype females showed a significant reduction in Inguinal Fat Pad weight normalized to body weight; this was accompanied by an increase in glucose compared with wildtype females shown by Student-Newman-Keuls Multiple Comparison test and Student's unpaired t tests. Our studies show that the GnRH-GnRHR system is not essential for growth or motor/sensory/orientation behavior during the first month of life prior to puberty onset. The lack of the GnRH-GnRHR axis, however, did affect females resulting in reduced subcutaneous Inguinal Fat Pad weight and increased glucose with possible insulin resistance; the loss of the normal rise of estradiol at postnatal days 15-28 may account for the altered metabolism in the prepubertal female pups.
Philippe Foubert - One of the best experts on this subject based on the ideXlab platform.
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autologous adipose derived regenerative cell therapy modulates development of hypertrophic scarring in a red duroc porcine model
Stem Cell Research & Therapy, 2017Co-Authors: Philippe Foubert, Diana Zafra, Mike Liu, Rohit Rajoria, Damian Gutierrez, Mayer Tenenhaus, John K. FraserAbstract:Effective prevention and treatment of hypertrophic scars (HTSs), a common consequence of deep-partial thickness injury, remain a significant clinical challenge. Previous studies from our group have shown that autologous adipose-derived regenerative cells (ADRCs) represent a promising approach to improve wound healing and, thereby, impact HTS development. The purpose of this study was to assess the influence of local delivery of ADRCs immediately following deep-partial thickness cutaneous injury on HTS development in the red Duroc (RD) porcine model. Bilateral pairs of deep-partial thickness excisional wounds (2 mm depth; 58 cm2 area) were created using an electric dermatome on RD pigs (n = 12). Autologous ADRCs were isolated from the Inguinal Fat Pad and then sprayed directly onto the wound at a dose of 0.25 × 106 viable cells/cm2. The paired contralateral wound received vehicle control. Wound healing and development of HTS were assessed over 6 months using digital imaging, quantitative measurement of skin hardness and pigmentation, and histology. Data showed that ADRC treatment led to reduced scar hyperpigmentation compared to control (p < 0.05). Using the Durometer, at 2 and 6 months post-injury, skin hardness was 10–20% lower in ADRCs-treated wounds compared to control vehicle (p < 0.05). A similar trend was observed with the skin fibrometer. ADRC treatment promoted more normal collagen organization, improvement in the number of rete ridges (p < 0.01), longer elastic fiber length (p < 0.01), and reduced hypervascularity (blood vessel density; p < 0.05). ADRC treatment was associated with modulation of IL-6 expression within the wound/scar with upregulation 2 weeks after injury (wound healing phase) and downregulation at 2 months (early scarring phase) post-treatment compared to control These findings support the potential therapeutic value of autologous ADRC administration for reduction of HTS development following deep-partial cutaneous injury.
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Autologous adipose-derived regenerative cell therapy modulates development of hypertrophic scarring in a red Duroc porcine model
BMC, 2017Co-Authors: Philippe Foubert, Diana Zafra, Mike Liu, Rohit Rajoria, Damian Gutierrez, Mayer Tenenhaus, John K. FraserAbstract:Abstract Background Effective prevention and treatment of hypertrophic scars (HTSs), a common consequence of deep-partial thickness injury, remain a significant clinical challenge. Previous studies from our group have shown that autologous adipose-derived regenerative cells (ADRCs) represent a promising approach to improve wound healing and, thereby, impact HTS development. The purpose of this study was to assess the influence of local delivery of ADRCs immediately following deep-partial thickness cutaneous injury on HTS development in the red Duroc (RD) porcine model. Methods Bilateral pairs of deep-partial thickness excisional wounds (2 mm depth; 58 cm2 area) were created using an electric dermatome on RD pigs (n = 12). Autologous ADRCs were isolated from the Inguinal Fat Pad and then sprayed directly onto the wound at a dose of 0.25 × 106 viable cells/cm2. The paired contralateral wound received vehicle control. Wound healing and development of HTS were assessed over 6 months using digital imaging, quantitative measurement of skin hardness and pigmentation, and histology. Results Data showed that ADRC treatment led to reduced scar hyperpigmentation compared to control (p
Ellen R Busby - One of the best experts on this subject based on the ideXlab platform.
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gonadotropin releasing hormone receptor gnrhr gene knock out normal growth and development of sensory motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice
PLOS ONE, 2017Co-Authors: Ellen R Busby, Nancy M SherwoodAbstract:Gonadotropin-releasing hormone (GnRH) is important in the control of reproduction, but its actions in non-reproductive processes are less well known. In this study we examined the effect of disrupting the GnRH receptor in mice to determine if growth, metabolism or behaviors that are not associated with reproduction were affected. To minimize the effects of other hormones such as FSH, LH and sex steroids, the neonatal-prepubertal period of 2 to 28 days of age was selected. The study shows that regardless of sex or phenotype in the Gnrhr gene knockout line, there was no significant difference in the daily development of motor control, sensory detection or spatial orientation among the wildtype, heterozygous or null mice. This included a series of behavioral tests for touch, vision, hearing, spatial orientation, locomotory behavior and muscle strength. Neither the daily body weight nor the final weight on day 28 of the kidney, liver and thymus relative to body weight varied significantly in any group. However by day 28, metabolic changes in the GnRH null females compared with wildtype females showed a significant reduction in Inguinal Fat Pad weight normalized to body weight; this was accompanied by an increase in glucose compared with wildtype females shown by Student-Newman-Keuls Multiple Comparison test and Student's unpaired t tests. Our studies show that the GnRH-GnRHR system is not essential for growth or motor/sensory/orientation behavior during the first month of life prior to puberty onset. The lack of the GnRH-GnRHR axis, however, did affect females resulting in reduced subcutaneous Inguinal Fat Pad weight and increased glucose with possible insulin resistance; the loss of the normal rise of estradiol at postnatal days 15-28 may account for the altered metabolism in the prepubertal female pups.