Bone marrow mesenchymal stem cell donors with a high body mass index display elevated endoplasmic reticulum stress and are functionally impaired

Abstract

Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.

Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

“…This may have a direct impact on their use, particularly in the field of regenerative medicine, where these cells could be potentially used for the treatment of orthopedic issues. It is conceivable that stem cells, obtained from very overweight donors, may display severe differentiation and proliferation defects, resulting in an isolated stem cell product of poor quality and decreased regenerative potential in vivo . An abnormal increase in fat mass results in dysfunctional AT, and consequently, AT‐MSCs are defective in differentiation, pro‐angiogenesis, motility, immunomodulation, and development of primary cilia, which are shortened and unable to properly respond to stimuli .…”

Challenges of heterotopic ossification—Molecular background and current treatment strategies

“…Not only aging but also obesity, a high‐fat diet, and type‐2 diabetes affect the function of MSCs. Hyperglycaemia and hyperinsulinaemia influence the microenvironment of the MSC niche, causing MSC exhaustion and dysfunction and reducing osteogenic differentiation . However, intensified adipogenesis increases the concentration of leptin, which regulates bone formation and can support osteogenesis .…”

Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells

“…Ronn and Colleagues showed the impact of both BMI and age on epigenetic modifications of genes candidate for metabolic diseases and cancer in human adipose tissue [ 88 ]. Moreover, the obese status, defined as BMI ≥ 30 kg/m 2 [ 68 , 69 ], negatively affects the properties of ADSCs [ 89 ] and both murine and human BM-MSCs [ 90 , 91 ]. Obesity and its associated inflammation promote dysregulation of both adipocytes and hADSC plasticity [ 92 ].…”