Autologous Adipocyte Derived Stem Cells Favour Healing in a Minipig Model of Cutaneous Radiation Syndrome

Abstract

Cutaneous radiation syndrome (CRS) is the delayed consequence of localized skin exposure to high doses of ionizing radiation. Here we examined for the first time in a large animal model the therapeutic potential of autologous adipose tissue-derived stroma cells (ASCs). For experiments, Göttingen minipigs were locally gamma irradiated using a 60Co source at the dose of 50 Gy and grafted (n = 5) or not (n = 8). ASCs were cultured in MEM-alpha with 10% fetal calf serum and basic fibroblast growth factor (2 ng.mL−1) and post irradiation were intradermally injected on days 25, 46, 67 and finally between days 95 and 115 (50×106 ASCs each time) into the exposed area. All controls exhibited a clinical evolution with final necrosis (day 91). In grafted pigs an ultimate wound healing was observed in four out of five grafted animals (day 130 +/− 28). Immunohistological analysis of cytokeratin expression showed a complete epidermis recovery. Grafted ASCs accumulated at the dermis/subcutis barrier in which they attracted numerous immune cells, and even an increased vasculature in one pig. Globally this study suggests that local injection of ASCs may represent a useful strategy to mitigate CRS.

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…Swine (specifically the G€ ottingen minipig) have been used as large animal models in medical research procedures and are now regarded as an appropriate animal model for many types of drug validation studies (Agay et al 2010;Forcheron et al 2012;Shim et al 2014;Singh et al 2016c). This is consistent with previous basic radiobiological investigations utilizing young, first-generation crosses of swine; e.g.…”

“…The latest treatment strategy relies on the excision of the affected tissue based on the reconstructed skin dose in order to prevent recurrent necrosis and is followed by therapy with autologous keratinocytes and combined with allogeneic stem cell administration (Lataillade et al 2007;Bey et al 2010). There has been an increased interest in using stromal cells/mesenchyml stem cells, progenitor cells, and adipose stromal cells for cell and gene therapy for treatment of cutaneous syndrome and H-ARS (Semont et al 2006;Lataillade et al 2007;Abdel-Mageed et al 2009;Agay et al 2010;Bey et al 2010;Saha et al 2011;Forcheron et al 2012;Singh et al 2014bSingh et al , 2014c. Swine have been used extensively to study the cutaneous effects of radiation exposure.…”

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…We also recommend using freshly cultured aMSCs in therapy rather than injecting justthawed frozen cells. Since we used syngenic cells, we support the use of autologous cells when available, as first choice therapy [79]. aMSCs dose size appears to be critical, since when it was increased beyond 2.5 million cells, we did not note any significant improvement but instead observed the opposite effect (5 million vs. 2.5 million frozen cells).…”

“…aMSCs are promising for cellular therapies due to their prominent anti-inflammatory effects, enhancing IL-10 secretion, ease of isolation, high cell count after expansion, as well as their source abundance [73]. In radiation-induced normal tissue injury, aMSCs have shown significant repair of cutaneous radiation syndrome [79][80][81][82][83] and photo-aging [84], RT-induced acute salivary gland [85] and intestine injuries [70,[86][87][88], and chronic injuries induced by radiotherapy [80,89]. In addition, we have shown in a previous study that aMSCs are relatively resistant to ionizing radiation, a property that qualifies them to be a reliable cellular therapy candidate before and during RT [159].…”

“…aMSCs have been investigated in many studies for cutaneous radiation syndrome [79][80][81][82][83] and photo-aging [84] with significant tissue repair. aMSCs systemic cell therapy led to significant restoration and improvement of acute salivary gland [85] and intestine injuries [70,[86][87][88] induced by ionizing radiation (IR).…”