Abstract
7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.
Highlights
Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic cells characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow (BM) failure and impaired normal hematopoiesis [1]
Human Mesenchymal stem cells (MSCs) were isolated from the BM of five patients with AML
Human MSCs were isolated from the BM of five patients interest: proliferation, multipotency, migration/homing, trophic capacity, immunosuppression, and with AML
Summary
Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic cells characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow (BM) failure and impaired normal hematopoiesis [1]. AML patients can be cured using conventional chemotherapy [2]. The incidence of AML increases exponentially with age, and the cure rate is significantly lower in older adults [3]. High levels of supportive care have improved patient outcomes, a high cure rate in AML has not yet been achieved [2]. Hematopoietic stem cells (HSCs) reside in the BM niche, a specialized microenvironment that contains complex and diverse stromal cell populations, mainly adipocyte cells and osteocyte [4]. Mesenchymal stem cells (MSCs) are multipotent cells that are found in the niche and generate most
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