Mesenchymal stem cells over-expressing cxcl12 enhance the radioresistance of the small intestine

Abstract

The chemokine C–X–C motif chemokine 12 (CXCL12) greatly impacts various biological processes in mammals, including cell survival, growth and migration. Mesenchymal stem cells (MSCs) are promising tools for carrying foreign genes to treat radiation-induced injuries in the intestinal epithelium. In this study, human adipose-derived MSCs were constructed to over-express the mouse cxcl12 gene to treat such injuries. In vitro, because of the high levels of mouse CXCL12 in conditioned medium produced by mouse cxcl12 gene-modified cells, phosphorylation of Akt at Ser473 and Erk1/2 at Thr202/Thr204 was increased within crypt cells of irradiated organoids compared with unmodified controls. Moreover, intracellular stabilization of β-catenin was achieved after treatment of mouse cxcl12 gene-modified cells with conditioned medium. As a result, survival of crypt cells was maintained and their proliferation was promoted. When delivering mouse cxcl12 gene-modified cells into irradiated BALB/c nude mice, mice were rescued despite the clearance of cells from the host within 1 week. Irradiated mice that received mouse cxcl12 gene-modified MSCs exhibited reduced serum levels of interleukin-1α (IL-1α) and IL-6 as well as elevated levels of CXCL12. Additionally, epithelial recovery from radiation stress was accelerated compared with the irradiated-alone controls. Moreover, mouse cxcl12 gene-modified MSCs were superior to unmodified cells at strengthening host repair responses to radiation stress as well as presenting increased serum CXCL12 levels and decreased serum IL-1α levels. Furthermore, the number of crypt cells that were positive for phosphorylated Akt at Ser473 and phosphorylated Erk1/2 at Thr202/Thr204 increased following treatment with mouse cxcl12 gene-modified MSCs. Thus, cxcl12 gene-modified MSCs confer radioresistance to the intestinal epithelium.

Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

“…20,21,70 Our lab and others have shown that irradiation causes an elevation of CXCL12 in the BM niche. [46][47][48] Here, we also observed reduced posttransplantation engraftment into irradiated CXCL12+ hosts ( Figure 4D and supplemental online Figure 3C). Hence, we hypothesized that overexpression of Cxcl12 provides protection to the host cells upon irradiation stress, thereby increasing the competition between the host and donor cells post-transplantation.…”

“…44 CXCL12 expression is increased upon irradiation in mice and zebrafish. [45][46][47][48] While loss-offunction and in vitro studies have shown that CXCL12 promotes quiescence of HSCs, it has also been demonstrated that CXCL12 improves the homing of HSCs to the BM in a transplantation setting. 6,[49][50][51] The aim of this study was to test the effects of elevated Cxcl12 levels in vivo.…”

The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy

“…Radiation also induces stromal production and secretion of TGF‐β in the TME, 54,55 and targeted inhibition of TGF‐β has been shown to confer radiosensitivity in breast and glioblastoma tumor models 35 . Other CAF‐secreted soluble factors including insulin‐like growth factor 2, PDGF, and CXCL‐12 have been implicated as mediators in overcoming radiation‐induced cell death 37,56,57 . The increased desmoplasia in response to RT also results in the development of chemoresistant tumors 47 .…”

Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

“…Elevated CXCL12 has been linked to tumor progression, along with increasing resistance to radiation and chemotherapy, and to immune suppression driven by the tumor microenvironment (Duda et al, 2011;Liu et al, 2014;Zboralski et al, 2017). Our lab and others have shown that irradiation causes an elevation of CXCL12 in the BM niche (Chang et al, 2009(Chang et al, , 2018Smith-Berdan et al, 2012). Here, we also observed reduced post-transplantation engraftment into irradiated CXCL12+ hosts ( Figure 4D and S3C).…”