Allogeneic Adipose-Derived Stem Cells Mitigate Acute Radiation Syndrome by the Rescue of Damaged Bone Marrow Cells from Apoptosis

Abstract

Acute radiation syndrome (ARS) is the radiation toxicity that can affect the hematopoietic, gastrointestinal, and nervous systems upon accidental radiation exposure within a short time. Currently, there are no effective and safe approaches to treat mass population exposure to ARS. Our study aimed to evaluate the therapeutic potential of allogeneic adipose-derived stem cells (ASCs) for total body irradiation (TBI)-induced ARS and understand the underlying mitigation mechanism. We employed 9.25 Gy TBI dose to C57BL/6 mice and studied the effect of allogeneic ASCs on mice survival and regeneration of the hematopoietic system. Our results indicate that intraperitoneal-injected ASCs migrated to the bone marrow, rescued hematopoiesis, and improved the survival of irradiated mice.Our transwell coculture results confirmed the migration of ASCs to irradiated bone marrow and rescue hematopoietic activity. Furthermore, contact coculture of ASCs improved the survival and hematopoiesis of irradiated bone marrow in vitro. Irradiation results in DNA damage, upregulation of inflammatory signals, and apoptosis in bone marrow cells, while coculture with ASCs reduces apoptosis via activation of DNA repair and the antioxidation system. Upon exposure to irradiated bone marrow cells, ASCs secrete prosurvival and hematopoietic factors, such as GM-CSF, MIP1α, MIP1β, LIX, KC, 1P-10, Rantes, IL-17, MCSF, TNFα, Eotaxin, and IP-10, which reduces oxidative stress and rescues damaged bone marrow cells from apoptosis. Our findings suggest that allogeneic ASCs therapy is effective in mitigating TBI-induced ARS in mice and may be beneficial for clinical adaptation to treat TBI-induced toxicities. Further studies will help to advocate the scale-up and adaptation of allogeneic ASCs as the radiation countermeasure.

Injectable bone marrow microniches by co-culture of HSPCs with MSCs in 3D microscaffolds promote hematopoietic reconstitution from acute lethal radiation

“…h-ARS not only damages HSPCs, but also adversely affects the BM's stromal cell and ECM [ 20 ]. To treat h-ARS, we developed a biomimetic BM microniches in vitro that recapitulated the porous structure and stiffness of the natural BM matrix, orchestrated with primary HSPCs and MSCs co-culture, to replace the irradiated BM through BM cavity administration.…”

“…Despite the unique 3D and porous structure, natural BM niche encompasses versatile supporting cells, such as MSCs, adipocytes, osteocytes, and endothelial cells which contribute to the maintenance of HSCs and HSPCs [ 19 ]. HSPCs and MSCs are the major stem cell sources for cell-based therapy that have shown good efficacy in ameliorating h-ARS [ 20 ]. MSCs niche supports hematopoiesis in the BM while facilitate HSPCs proliferation under allogeneic microenvironments [ 21 ].…”

Metformin Improves Stemness of Human Adipose-Derived Stem Cells by Downmodulation of Mechanistic Target of Rapamycin (mTOR) and Extracellular Signal-Regulated Kinase (ERK) Signaling

“…In addition to mTOR, the ERK signaling pathway plays a crucial role in proliferation and adipogenesis. Xiaomin Ning et al, in their publication, posit that adipogenesis is activated by ERK signaling [ 58 ]. Since we observed that metformin inhibited adipogenesis and proliferation, we decided to investigate the effect of metformin on ERK signaling.…”

Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells

“…The isolation of adipose precursor cells was performed as follows [ 31 ]. Adipose tissue biopsies obtained after surgical procedures were aseptically transferred to the laboratory in sterile sealed tubes.…”