Autologous Bone Marrow Mesenchymal Stem Cells Improve the Quality and Stability of Vascularized Flap Surgery of Irradiated Skin in Pigs

Abstract

Cutaneous radiation syndrome has severe long‐term health consequences. Because it causes an unpredictable course of inflammatory waves, conventional surgical treatment is ineffective and often leads to a fibronecrotic process. Data about the long‐term stability of healed wounds, with neither inflammation nor resumption of fibrosis, are lacking. In this study, we investigated the effect of injections of local autologous bone marrow‐derived mesenchymal stromal cells (BM‐MSCs), combined with plastic surgery for skin necrosis, in a large‐animal model. Three months after irradiation overexposure to the rump, minipigs were divided into three groups: one group treated by simple excision of the necrotic tissue, the second by vascularized‐flap surgery, and the third by vascularized‐flap surgery and local autologous BM‐MSC injections. Three additional injections of the BM‐MSCs were performed weekly for 3 weeks. The quality of cutaneous wound healing was examined 1 year post‐treatment. The necrotic tissue excision induced a pathologic scar characterized by myofibroblasts, excessive collagen‐1 deposits, and inadequate vascular density. The vascularized‐flap surgery alone was accompanied by inadequate production of extracellular matrix (ECM) proteins (decorin, fibronectin); the low col1/col3 ratio, associated with persistent inflammatory nodules, and the loss of vascularization both attested to continued immaturity of the ECM. BM‐MSC therapy combined with vascularized‐flap surgery provided mature wound healing characterized by a col1/col3 ratio and decorin and fibronectin expression that were all similar to that of nonirradiated skin, with no inflammation, and vascular stability. In this preclinical model, vascularized flap surgery successfully and lastingly remodeled irradiated skin only when combined with BM‐MSC therapy. Stem Cells Translational Medicine 2018:569–582

Long-term effectiveness of local BM-MSCs for skeletal muscle regeneration: a proof of concept obtained on a pig model of severe radiation burn

“…This study concerned the same animals previously described [ 13 ] and included eight pigs divided into two groups: four irradiated pigs received a fasciocutaneous perforator flap (flap-only group), while four other irradiated pigs received this flap as well as repeated local administrations of autologous bone marrow-derived MSCs (flap-MSC group) (Fig. 1a ).…”

“…As previously described [ 13 ], the cells were isolated, expanded, and characterized in clinical-grade porcine MSCs. The cells were delivered (from passage 0 of the first bone marrow collection, BM1) locally into the wound bed.…”

“…1a ). We previously report [ 13 ] that these cells were positive (> 90%) for CD90, CD29, CD44, and SLA-1 surface markers and cells differentiated into adipocytes, osteoblasts, and chondrocytes when cultured in medium that was simultaneously osteogenic, adipogenic, and chondrogenic.…”

“…The unpredictable spatiotemporal course of the substantial inflammatory waves due to irradiation raises two primary questions: regeneration and long-term maintenance of healing, either without inflammation and/or with renewed fibrosis. We recently showed in a preclinical model that irradiated skin could be successfully and lastingly remodeled after excision of necrotic cutaneous tissue by vascularized flap surgery combined with BM-MSC treatment [ 13 ]. In this study, we investigated the long-term effects of post-irradiation treatment by bone marrow-derived MSCs on muscle regenerative capacity, muscle fibrosis, and angiogenesis in a large preclinical model after surgical excision and debridement of necrotic tissue (skin and muscle).…”

Oxygen and nutrient delivery in tissue engineering: Approaches to graft vascularization

“…MSCs in particular have shown a great potential in aiding vascularization in regenerative medicine, most likely by a combination of their immunomodulatory effects and their paracrine release of growth factors, such as vascular endothelial growth factor (VEGF; Andrzejewska, Lukomska, & Janowski, n.d.; Shafiee et al, ). This enhanced vascularization has been shown effective, for example, in hydrogels for wound healing (Alapure et al, ), in vascular flaps (Linard et al, ), periosteal flaps (Nau et al, ), and bone scaffolds (Rottensteiner‐Brandl et al, ).…”