Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities

Abstract

Background: Recent studies have demonstrated mesenchymal stem cells (MSCs) as effective mitochondrial donors with therapeutic success in multiple experimental models of human disease. MSCs obtained from different tissue sources such as bone marrow (BM), adipose (AD), dental pulp (DP), and Wharton's jelly (WJ) are routinely used in clinical trials with no known study of their mitochondrial donor capacity. Here, we show for the first time that MSCs derived from different tissue sources have different mitochondrial donor properties and that this is correlated with their intrinsic respiratory states. Methods: MitoTracker®-labeled MSCs were co-cultured with Cell Trace-labeled U87-MG cells or rat cardiomyocytes. Mitochondrial transfer abilities of MSCs were assessed by using flow cytometry analysis and fluorescence imaging. Mitochondrial reactive oxygen species (mtROS) levels were analyzed by using MitoSOX red-based staining, and mitochondrial respiration parameters were analyzed by using a Seahorse XF Analyzer. Results: AD-MSCs and BM-MSCs displayed higher mitochondrial transfer than DP-MSCs and WJ-MSCs. Counterintuitively, DP-MSCs and WJ-MSCs were more effective in suppressing mtROS levels in stressed recipient cells than AD-MSCs or BM-MSCs. Interestingly, the oxygen consumption rates and intrinsic mitochondrial respiration parameters like ATP levels, basal and maximal respiration, and mitochondrial DNA copy number in donor MSCs showed a highly significant inverse correlation with their mitochondrial donation. Conclusions: We find that there are intrinsic differences in the mitochondrial respiration, donation capacity, and therapeutic efficacy among MSCs of different tissue origin. MSCs with high mitochondrial respiration capacities are associated with lower mitochondrial transfer but more effective suppression of mtROS in stressed recipient cells. This is most compatible with a model where recipient cells optimally regulate mitochondrial transfer such that they take more mitochondria from MSCs with lower mitochondrial function. Furthermore, it appears to be advantageous to use MSCs such as DP-MSCs or WJ-MSCs with higher mitochondrial respiratory abilities that achieved better therapeutic effect with lower mitochondrial transfer in our study. This opens up a new direction in stem cell therapeutics.