Repeated Autologous Bone Marrow-Derived Mesenchymal Stem Cell Injections Improve Radiation-Induced Proctitis in Pigs

Abstract

The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.

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

“…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). Furthermore, aMSCs have shown promise for successful cell therapy in chronic radiotherapy-induced injuries [80,89].…”

“…In addition, aMSCs systemic cell therapy has shown significant restoration and improvement of acute salivary gland [85] and intestine injuries [70,[86][87][88] induced by ionizing radiation (IR). Furthermore, aMSCs showed a promising potential of being a successful cell therapy option in chronic injuries induced by radiotherapy as well [80,89].…”

Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy?

“…These immunomodulatory properties of MSCs are of special importance in the treatment of IBD. Systemic administration of bone marrow MSCs in a mouse model of chemical-induced colitis [43] and in a pig model of radiation-induced proctitis [44] , down-regulated autoimmune and inflammatory responses, and as a consequence, facilitated tissue regeneration. The experience in luminal CD is limited (Table 2).…”

Treatment of radiation-induced acute intestinal injury with bone marrow-derived mesenchymal stem cells

“…The limitations of radiotherapy, in particular radiation injury to the gastrointestinal tract, have produced an urgent requirement for novel and effective treatments for radiation damage (2). Previous studies have shown that mesenchymal stem cells (MSCs) are able to promote the repair of intestinal structures and functions, indicating their potential for the treatment of intestinal radiation injury (3)(4)(5).…”