Generation of tissue-specific cells from MSC does not require fusion or donor-to-host mitochondrial/membrane transfer

Abstract

Human mesenchymal stem cells (MSC) hold great promise for cellular replacement therapies. Despite their contributing to phenotypically distinct cells in multiple tissues, controversy remains regarding whether the phenotype switch results from a true differentiation process. Here, we studied the events occurring during the first 120 h after human MSC transplantation into a large animal model. We demonstrate that MSC, shortly after engrafting different tissues, undergo proliferation and rapidly initiate the differentiative process, changing their phenotype into tissue-specific cells. Thus, the final level of tissue-specific cell contribution is not determined solely by the initial level of engraftment of the MSC within that organ, but rather by the proliferative capability of the ensuing tissue-specific cells into which the MSC rapidly differentiate. Furthermore, we show that true differentiation, and not cell fusion or transfer of mitochondria or membrane-derived vesicles between transplanted and resident cells, is the primary mechanism contributing to the change of phenotype of MSC upon transplantation.

The hematopoietic system in the context of regenerative medicine

“…In some cases, such as the FAH model, it appears that the donor-derived hepatocytes are generated almost entirely through the process of cell fusion, in which the transplanted HSC fuse with the host’s endogenous hepatocytes, generating cells that morphologically and phenotypically appear to be hepatocytes, yet contain the DNA from both the donor HSC and the host hepatocytes [292, 307, 314]. In other models, including the non-injury fetal sheep model, the hepatocytes appear to be generated almost exclusively through what seems to be true reprogramming/trans-differentiation of the transplanted cells into hepatocytes without exchange of any genetic or cellular elements between the host and the engrafted human cells [293, 297, 306, 308, 315, 316]. Another important caveat is that the phenotype and purity of the cell population transplanted also plays a role in whether hepatocytes are generated and, if so, whether donor-host cell fusion occurs [317–320].…”

Periocular and Intra-Articular Injection of Canine Adipose-Derived Mesenchymal Stem Cells: An In Vivo Imaging and Migration Study

“…11 One possible therapeutic approach for treatment of immune mediated disorders is the use of mesenchymal stem cells (MSCs). MSCs are adult-derived stem cells that can be obtained from a variety of tissue sources including bone marrow 12,13 and adipose tissue. [14][15][16] Adipose-derived (Ad) MSCs have been isolated and characterized from several animal species including dogs.…”

Potential of Mesenchymal Stem Cells for Liver Regeneration

“…Using the fetal sheep model made it possible for us to show that MSC could give rise directly to cells within the liver without the need for first forming hematopoietic elements [41]. In more recent studies, we have now shown that the ability to directly contribute to liver repopulation without the need for a hematopoietic intermediate enables the transplanted MSC to rapidly begin contributing to the growing liver, producing cells with hepatic markers within as little as 24 or 48 hours post-transplantation [41].…”

“…In more recent studies, we have now shown that the ability to directly contribute to liver repopulation without the need for a hematopoietic intermediate enables the transplanted MSC to rapidly begin contributing to the growing liver, producing cells with hepatic markers within as little as 24 or 48 hours post-transplantation [41]. The findings of these more recent studies confirmed our prior findings regarding the lack of a need for fusion, and furthered our understanding of the mechanism of hepatic repopulation by demonstrating that the generation of hepatocytes occurs independently of the transfer of either mitochondria or membrane-derived vesicles between the transplanted donor cells and the cells of the recipient liver [41]. These findings thus provide strong evidence to support genetic reprogramming and differentiation of the transplanted stem cells.…”