Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development.

cells Review Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt Pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development Pietro Gentile 1, * 1 2 * and Simone Garcovich 2 Surgical Science Department, Plastic and Reconstructive Surgery Unit, University of “Tor Vergata”, 00133 Rome, Italy Institute of Dermatology, F. Policlinico Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; Correspondence: ; Tel.: +39-3388515479 Received: 2 April 2019; Accepted: 14 May 2019; Published: 16 May 2019



 Abstract: The use of stem cells has been reported to improve hair regrowth in several therapeutic strategies, including reversing the pathological mechanisms, that contribute to hair loss, regeneration of hair follicles, or creating hair using the tissue-engineering approach. Although various promising stem cell approaches are progressing via pre-clinical models to clinical trials, intraoperative stem cell treatments with a one-step procedure offer a quicker result by incorporating an autologous cell source without manipulation, which may be injected by surgeons through a well-established clinical practice. Many authors have concentrated on adipose-derived stromal vascular cells due to their ability to separate into numerous cell genealogies, platelet-rich plasma for its ability to enhance cell multiplication and neo-angiogenesis, as well as human follicle mesenchymal stem cells. In this paper, the significant improvements in intraoperative stem cell approaches, from in vivo models to clinical investigations, are reviewed. The potential regenerative instruments and functions of various cell populaces in the hair regrowth process are discussed. The addition of Wnt signaling in dermal papilla cells is considered a key factor in stimulating hair growth. Mesenchymal stem cell-derived signaling and growth factors obtained by platelets influence hair growth through cellular proliferation to prolong the anagen phase (FGF-7), induce cell growth (ERK activation), stimulate hair follicle development (β-catenin), and suppress apoptotic cues (Bcl-2 release and Akt activation). Keywords: stem cell therapy; stem cell hair loss; human follicle stem cells; platelet-rich plasma; hair loss; hair regrowth; PRP hair; stem cells hair 1. Introduction Hair tissue engineering and stem cell therapy are new approaches to treating hair loss (HL). Methods using exogenous cell sources or progenitor cells (PCs) are being tested in cell treatment clinical trials. These trials incorporate cells obtained from allogeneic and autologous sources. Specifically, intra-surgical cell treatments that incorporate autologous cell-based treatments with a one-step approach (cell harvesting, minimal manipulation, and immediate injection) into a single technique offer tremendous potential; a few methodologies have achieved clinical application. The intra-surgical cell treatment process involves tissue collection and preparation to obtain the desired cell product, followed by careful evaluation using the clinical application, and then cell conveyance. Intra-surgical Cells 2019, 8, 466; doi:10.3390/cells8050466 www.mdpi.com/journal/cells Cells 2019, 8, 466 2 of 21 cell treatment benefits from the availability and safety of using the patient’s own cells, which do not trigger an adverse reaction, as well as from the numerous important cell types that can be harvested using minimally invasive strategies [1]. This treatment bypasses a significant number of restrictions associated with exogenous cell treatment by avoiding in vitro cell control and expensive cell extension, the requirement for good manufacturing practice (GMP) facilities, the need to procure a work force for cell culture preparation, the potential for pollution, and a second method (at an alternate time point) to collect the cells. It might be helpful to maintain a strategic distance from the cell culture to restrict phenotype changes that may occur when cells are expelled from their local microenvironment for an all-encompassing time period [1]. Additionally, the techniques are entirely performed inside the surgical room (in absence of culture growth), which may lessen the hold-up time for the medical procedure. The U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other administrative specialists consider grown-up cell products as biological products that can be partitioned into two classes: minimally manipulated biological products (obtained through centrifugation, filtration, and isolation without cell expansion) and manipulated biological products (obtained through culture-expanded stem cells). Certain intraoperative cell approaches fit the minimally-manipulated biological product category in which broad clinical trials are not required, consequently speeding up potential interpretation to facilities. 2. Hair Loss and Androgenic Alopecia: Bio-Molecular Pathway Disorder HL is determined by an assortment of factors: inherited (trichodystrophy and androgenetic alopecia), accompanying comorbidity conditions, hormonal clutters (thyroid organ disease, insulin resistance), immune system (patchy alopecia and lupus erythematous), nutritional scatters, environmental elements (drugs, ultraviolet (UV) radiation), mental disorders (stress and trichotillomania), and aging. Harming factors influence the hair cycle (HC) and reduce stem cell activity and hair follicle recovery capacity [2]. A clinical need exists for the advancement of biotechnology to enhance hair growth to address the HL issue, specifically, in cases of androgenic alopecia (AGA). AGA is a dynamic and incessant HL issue affecting 80% of white males and 40% of white females below the age of 70, in which lymphocytes and mast cells have been identified around the miniaturizing follicle in the stem-cell-rich knot zone [3–6]. The scaling down of the follicles (i.e., miniaturization) is characterized by a depletion of the anagen stage, with an enhancement in the measure of resting hair follicles (HF), telogen, and the presence of infinitesimal hairs on a bald scalp [5–7]. Current drugs available to treat AGA include medications such as Finasteride® ; topical moisturizers such as Minoxidil® , and surgical procedures such as hair transplantation [4]. In HL scalps, the hair follicle stem cell numbers remain unaltered; however, the quantity of the more effectively multiplying PCs significantly decreases [7]. Along these lines, the aim of hair tissue engineering is developing new autologous advancements to induce hair regrowth by in vitro and ex vivo cultures or by in vivo recovery and bio-stimulation. Autologous stem cells (SCs) have been of particular interest for application in hair regrowth. Some early endeavors in the field concentrated on disengaging essential cells from a biopsy of the scalp tissue and maturing the cells ex vivo for a resultin (...truncated)