Mesenchymal stromal cells may promote lipid utilization via increment of mitochondria biogenesis in targeted hepatocytes

Question:

In an in vitro model of fatty liver, human bone marrow-derived mesenchymal stromal cells (MSC) upregulated genes involved in lipid utilization and, thus reduced the lipid content in the mouse hepatocytes by a mechanism independent of paracrine signaling. Instead, hepatocytes were touched by long filopodium-like, actin- and mitochondria-containing tunneling nanotubes (TNT) derived from MSC. Indeed, the expression of human microtubule motor proteins and related adaptors, namely kinesin family member 5B (KIF5B) and mitochondrial Rho GTPase 1 (MIRO1), were increased in co-culture as compared with MSC alone. We aim to identify the mechanism involved mitigation of hepatocytic lipid load by MSC.

Methods:

Mono- and co-cultures of primary mouse hepatocytes and human bone marrow-derived MSC were grown in steatosis-inducing methionine-choline-deficient (MCD) medium. To understand the involvement of actin, a major component of TNT, expression of genes involved in actin-dependent TNT transportation and of markers involved in mitochondria biogenesis was examined by RT-PCR using human- and mouse-specific primer pairs.

Results:

Compared with MSC alone, the co-culture of hepatocytes and MSC did not impact on inducers of actin-based TNT, namely TNFα-induced protein 2 (TNFAIP2) and RAS like proto-oncogene A (RALA), in the MSC. Neither PPARγ coactivator 1α (PPARGC1A; PGC1α) nor other markers of mitochondrial biogenesis such as mitochondrial transcription factor A (TFAM) and heme oxygenase-1 (HMOX1) were altered in the MSC. Yet, in the mouse hepatocytes, the expression of PGC1α, a regulator of mitochondria biogenesis, was enhanced in co-culture as compared with hepatocytes alone.

Conclusion:

Human MSC may increase the degradation of lipids in mouse hepatocytes by mitochondria transfer from the MSC to the hepatocytes via TNT. Transport may be achieved by microtubule-based, but not actin-based cargo transport. The delivered human mitochondria may induce the biogenesis of mitochondria in the mouse hepatocytes, and thus elevate the expression of genes involved in fatty acid oxidation to elicit lipid utilization. Thus, the results presented here may support the potential of MSC-derived mitochondria transplantation to foster lipid breakdown in fatty livers.

Work was supported by funding through the DFG by a grant (CH 109/22 – 1) to BC.