Stem Cell and Stromal Vascular Fraction Treatment for Penile Tunica Albuginea and Urethral Fibrosis

Fibrosis is a wound healing disorder and it is defined by the excessive accumulation of fibrous connective tissue, such as collagen and fibronectin, in and around inflamed or damaged tissue. Although collagen and fibronectin deposition is an indispensable and, typically, reversible part of wound healing, normal tissue repair can evolve into a progressively irreversible fibrotic response if the tissue injury is severe or repetitive or if the wound-healing response itself becomes deregulated (1).Fibrosis represents the final, common pathological outcome of many chronic inflammatory diseases. Fibrosis can be promoted by different events and it can lead to permanent scarring and dysfunction in different organs as seen in end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis and heart failure (1).Regardless of the initiating events and target organ, a common feature to all fibrotic diseases is the fibroblast-to-myofibroblast differentiation, which are the key mediators of fibrotic tissue remodelling (1). Interesting, it is now clear that many elements of the innate and adaptive immune response participate in the differentiation and activation of fibroblasts. From this point of view, fibrosis could be considered as the result of a severe or repetitive injury and an altered host response to injury itself (1).Despite the knowledge of the fibrotic process, there is not an efficacious treatment available in the clinical setting. For this reason the research of new treatments was improved in the last decades. There is now increasing evidence for the role of Mesenchymal Stem Cells (MSCs) as potential treatment strategy to alleviate fibrosis (2). MSCs have been described as being able to give rise to several, quite different cell phenotypes. However, the ability to differentiate is not the only characteristic that makes these cells attractive for therapeutic purposes (3). The secretion of a broad range of bioactive molecules by MSCs, such as growth factors, cytokines and chemokines, constitutes their most biologically significant role under injury condition (4). The exact mechanisms of the antifibrotic effects of MSCs remain to be elucidated (2). Most preclinical studies suggest that MSC work through immunomodulation, thereby limiting the host response to injury and preventing the onset of fibrosis (3). Another proposed mechanism is the induction of phenotypical changes in resident fibroblast illustrated by reduced collagen and increased hyaluronic acid production in fibroblasts co-cultured with MSC. Furthermore, the direct interaction of MSC with the extracellular matrix has been proposed based on their ability to secrete high numbers of matrix metalloproteinase and other matrix-modulating enzymes (3).MSCs are adult stem cells traditionally found in the bone marrow. However, mesenchymal stem cells can also be isolated from other tissues including cord blood, peripheral blood, fallopian tube, fetal liver, lung and adipose tissue. Adipose tissue is a multifunctional organ that contains various cellular types, such as mature adipocytes and the stromal vascular fraction (SVF) (5). The adipose SVF provides a rich source of adipose-derived stem cells (ADSCs) and can easily be isolated from human adipose tissue, representing a viable alternative to bone marrow mesenchymal stem cells (5). The SVF can be easily isolated through enzymatic digestion of aspirated adipose tissue and it does not need to be cultured. From a clinical standpoint, however, it would be more advantageous to use freshly isolated, whole SVF than to use isolated and expanded ADSCs because isolating and culturing the ADSCs requires facilities and personnel, and possesses a risk of patient exposure to foreign serum and undefined proteins (5).MSCs have been shown to play a role in decreasing fibrosis in animal models of idiopathic lung fibrosis, liver fibrosis, kidney fibrosis and heart ischemia. Also to date, approximately 79 clinical trials are on-going evaluating the effectiveness of the MCS on various forms of fibrosis i.e. liver fibrosis, fibrosis in Crohn disease, cardiac fibrosis, pulmonary fibrosis (http://clinicaltrials.gov)..Peyronie's disease (PD) and the urethral stricture represent localized connective tissue disorders characterized by changes in collagen composition of the tunica albuginea of the corpus cavernosum and of the urethral corpus spongiosum (6-9). The consequences of these conditions can enormously impair the patient's quality of life by causing micturition disturbances (urethral strictures) or impairment of erectile function and erection-related pain (PD) (6-9). While various surgical options are currently being explored, for both diseases, with limited success-rates, conservative therapies are generally lacking efficacy (6-9) ObjectiveGeneral aim: To evaluate the efficacy local injection of human ADSCs (hADSCs) and autologous SVF as a treatment of urethral stricture and PD using a rat animal model of the diseases;Specific aim 1: To establish and validate a new model of urethral stricture in rat. Specific aim 2: To study the efficacy of hADSCs local injection in the development of urethral fibrosis in a rat model of urethral stricture;Specific aim 3: To study the efficacy of hADSCs periurethral injection in preventing bladder dysfunction in a rat model of urethral stricture development;Specific aim 4: To study the efficacy of hADSCs local injection in the development of tunica albuginea fibrosis in a rat model of PD;Specific aim 5: To study the efficacy of hADSCs local injection in established tunica albuginea fibrosis in a rat model of PD;Specific aim 6: To study the efficacy of autologous SVF local injection in the development of tunica albuginea fibrosis in a rat model of PD;Specific aim 7: To study the efficacy of autologous SVF local injection in established tunica albuginea fibrosis in a rat model of PD;Reference Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012 Jul 6;18(7):1028-40. doi: 10.1038/nm.2807. Review.Jackson WM, Nesti LJ, Tuan RS. Mesenchymal stem cell therapy for attenuation of scar formation during wound healing. Stem Cell Res Ther. 2012 May 31;3(3):20.Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):419-27.Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal Stem Cells in Tissue Repair. Front Immunol. 2013 Sep 4;4:201. eCollection 2013. Review.Gentile P, Orlandi A, Scioli MG, Di Pasquali C, Bocchini I, Cervelli V. Concise review: adipose-derived stromal vascular fraction cells and platelet-rich plasma: basic and clinical implications for tissue engineering therapies in regenerative surgery. Stem Cells Transl Med. 2012 Mar;1(3):230-6.Albersen M, Kendirci M, Van der Aa F, Hellstrom WJ, Lue TF, Spees JL. Multipotent stromal cell therapy for cavernous nerve injury-induced erectile dysfunction. J Sex Med. 2012 Feb;9(2):385-403.Levine LA, Burnett AL. Standard operating procedures for Peyronie's disease. JSex Med. 2013 Jan;10(1):230-44. doi: 10.1111/j.1743-6109.2012.03003.x. Epub 2012 Dec 4.Lee YJ, Kim SW. Current Management of Urethral Stricture. Korean J Urol. 2013 Sep;54(9):561-569. Epub 2013 Sep 10. Review.Baskin LS, Constantinescu SC, Howard PS et al. Biochemical characterisation and quantification of the collagenous components of urethral stricture tissue. J Urol 1993; 150: 642-7

Jaar van publicatie:2019