Systemically delivered adipose stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome by immunomodulating the inflammatory response through a CD11b+ cell-dependent mechanism

Lydia Bensemmane; Fabien Milliat; Xavier Treton; Christine Linard

doi:10.1186/s13287-023-03562-7

Systemically delivered adipose stromal vascular fraction mitigates radiation-induced gastrointestinal syndrome by immunomodulating the inflammatory response through a CD11b⁺ cell-dependent mechanism

Stem Cell Res Ther. 2023 Nov 13;14(1):325. doi: 10.1186/s13287-023-03562-7.

Authors

Lydia Bensemmane¹, Fabien Milliat¹, Xavier Treton², Christine Linard³

Affiliations

¹ PSE-SANTE/SERAMED/LRMed, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 92260, Fontenay-Aux-Roses, France.
² Institut Des MICI, 92200, Neuilly, France.
³ PSE-SANTE/SERAMED/LRMed, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 92260, Fontenay-Aux-Roses, France. christine.linard@irsn.fr.

Abstract

Background: Stromal vascular fraction (SVF) treatment promoted the regeneration of the intestinal epithelium, limiting lethality in a mouse model of radiation-induced gastrointestinal syndrome (GIS). The SVF has a heterogeneous cell composition; the effects between SVF and the host intestinal immunity are still unknown. The specific role of the different cells contained in the SVF needs to be clarified. Monocytes-macrophages have a crucial role in repair and monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2.

Methods: Mice exposed to abdominal radiation (18 Gy) received a single intravenous injection of SVF (2.5 × 10⁶ cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Intestinal immunity and regeneration were evaluated by flow cytometry, RT-PCR and histological analyses.

Results: Using flow cytometry, we showed that SVF treatment modulated intestinal monocyte differentiation at 7 days post-irradiation by very early increasing the CD11b⁺Ly6C⁺CCR2⁺ population in the intestine ileal mucosa and accelerating the phenotype modification to acquire CX3CR1 in order to finally restore the F4/80⁺CX3CR1⁺ macrophage population. In CX3CR1-depleted mice, SVF treatment fails to mature the Ly6C^-MCHII⁺CX3CR1⁺ population, leading to a macrophage population deficit associated with proinflammatory environment maintenance and defective intestinal repair; this impaired SVF efficiency on survival. Consistent with a CD11b⁺ being involved in SVF-induced intestinal repair, we showed that SVF-depleted CD11b⁺ treatment impaired F4/80⁺CX3CR1⁺macrophage pool restoration and caused loss of anti-inflammatory properties, abrogating stem cell compartment repair and survival.

Conclusions: These data showed that SVF treatment mitigates the GIS-involving immunomodulatory effect. Cooperation between the monocyte in SVF and the host monocyte defining the therapeutic properties of the SVF is necessary to guarantee the effective action of the SVF on the GIS.

Keywords: Intestine; Irradiation; Monocyte; Stromal vascular fraction.

MeSH terms

Adipose Tissue
Animals
Intestines
Macrophages
Mice
Monocytes*
Radiation Injuries, Experimental* / therapy
Stromal Cells
Stromal Vascular Fraction*