Transfer Of Organelles Research Articles

MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking.

Tunneling nanotubes (TNTs) are actin‐rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down‐regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F‐actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV‐Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.

Effects of Tunneling Nanotubes on the Mitochondrial Regulation of the Amount and Subcellular Localization of Β-Catenin During Osteogenesis of MSC/HUVEC Spheroids

Tunneling nanotubular expressways (TNTs), which allow direct cell-to-cell transfer of intracellular organelles, have been widely identified in various cell types. However, the precise functions of TNTs in intercellular communication and their practical application in tissue regeneration is still uncertain. Mesenchymal stem cells (MSCs) are commonly employed as seed cells in tissue engineering. The differentiation of MSCs requires sufficient energy, which can be regulated by the fusion and fission of mitochondria. The phenomenon of mitochondrial shuttle between cells has been observed, and has led to the hypothesis that applying TNTs to deliver mitochondria into MSCs might be a promising approach to stimulate osteogenic differentiation. In proliferating endothelial cells (ECs), cellular dynamics including the fusion and fission of mitochondria is increased, and thus ECs are considered as ideal candidates for mitochondria donors. In order to exploit the application of TNT-mediated mitochondria transfer, we employed mesenchymal stem cell/ human umbilical vein endothelial cell (MSC/HUVEC) spheroids as a research model, and investigated the transfer among them, as well as the underlying mechanism. Fluorescence staining showed that directional transfer of mitochondria between MSC-HUVEC pairs, especially from HUVEC to MSC. Through TNT-mediated mitochondrial transfer, osteogenesis markers were up-regulated, accompanied by an increased amount of β-catenin in MSCs. Moreover, the improved generation of pre-vascular network has also been observed in the spheroids, as a result of β-catenin translocation to the periphery of HUVECs. However, all of these effects are abolished by the destruction of TNTs. Collectively, our results indicate that the TNT strategy can be applied widely to various aspects of biological research, such as but not limited to tissue regeneration and targeted drug delivery.

Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.

Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.

Transfer of mitochondria and endosomes between cells by gap junction internalization

Intercellular organelle transfer has been documented in several cell types and has been proposed to be important for cell-cell communication and cellular repair. However, the mechanisms by which organelle transfer occurs are uncertain. Recent studies indicate that the gap junction protein, connexin 43 (Cx43), is required for mitochondrial transfer but its specific role is unknown. Using three-dimensional electron microscopy and immunogold labeling of Cx43, this report shows that whole organelles including mitochondria and endosomes are incorporated into double-membrane vesicles, called connexosomes or annular gap junctions, that form as a result of gap junction internalization. These findings demonstrate a novel mechanism for intercellular organelle transfer mediated by Cx43 gap junctions.

Mitochondria Transfer in Bone Marrow Hematopoietic Activity.

The well-established crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for the homeostasis and hematopoietic regeneration in response to blood formation emergencies. Past decade has witnessed that the intercellular communication mediated by the transfer of cytoplasmic material and organelles between cells can regenerate and/or repair the damaged cells. Mitochondria have recently emerged as a potential regulator of HSC fate. This review intends to discuss recent advances in the understanding of the mitochondrial dynamics, specifically focused on the role of mitochondrial transfer, in the maintenance of HSC activity with clear implications in stem cell transplantation and regenerative medicine. HSC are highly heterogeneous in their mitochondrial metabolism, and the quiescence and potency of HSC depend on the status of mitochondrial dynamics and the clearance of damaged mitochondria. Recent evidence has shown that in stress response, BM stromal cells transfer healthy mitochondria to HSC, facilitate HSC bioenergetics shift towards oxidative phosphorylation, and subsequently stimulate leukocyte expansion. Furthermore, metabolic rewiring following mitochondria transfer from HSPC to BM stromal cells likely to repair the damaged BM niche and accelerate limiting HSC transplantation post myeloablative conditioning.

Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling.

Cellular senescence is a state of irreversible cell proliferation arrest induced by various stressors including telomere attrition, DNA damage, and oncogene induction. While beneficial as an acute response to stress, the accumulation of senescent cells with increasing age is thought to contribute adversely to the development of cancer and a number of other age-related diseases, including neurodegenerative diseases for which there are currently no effective disease-modifying therapies. Non-cell-autonomous effects of senescent cells have been suggested to arise through the SASP, a wide variety of proinflammatory cytokines, chemokines, and exosomes secreted by senescent cells. Here, we report an additional means of cell communication utilised by senescent cells via large numbers of membrane-bound intercellular bridges—or tunnelling nanotubes (TNTs)—containing the cytoskeletal components actin and tubulin, which form direct physical connections between cells. We observe the presence of mitochondria in these TNTs and show organelle transfer through the TNTs to adjacent cells. While transport of individual mitochondria along single TNTs appears by time-lapse studies to be unidirectional, we show by differentially labelled co-culture experiments that organelle transfer through TNTs can occur between different cells of equivalent cell age, but that senescent cells, rather than proliferating cells, appear to be predominant mitochondrial donors. Using small molecule inhibitors, we demonstrate that senescent cell TNTs are dependent on signalling through the mTOR pathway, which we further show is mediated at least in part through the downstream actin-cytoskeleton regulatory factor CDC42. These findings have significant implications for the development of senomodifying therapies, as they highlight the need to account for local direct cell-cell contacts as well as the SASP in order to treat cancer and diseases of ageing in which senescence is a key factor.

Human Mesenchymal Stem Cells: The Present Alternative for High-Incidence Diseases, Even SARS-Cov-2.

Mesenchymal stem cells (MSCs), defined as plastic adherent cells with multipotent differentiation capacity in vitro, are an emerging and valuable tool to treat a plethora of diseases due to their therapeutic mechanisms such as their paracrine activity, mitochondrial and organelle transfer, and transfer of therapeutic molecules via exosomes. Nowadays, there are more than a thousand registered clinical trials related to MSC application around the world, highlighting MSC role on difficult-to-treat high-incidence diseases such as the current COVID-19, HIV infections, and autoimmune and metabolic diseases. Here, we summarize a general overview of MSCs and their therapeutic mechanisms; also, we discuss some of the novel clinical trial protocols and their results as well as a comparison between the number of registries, countries, and search portals.

Mitochondrial transplantation-a possible therapeutic for mitochondrial dysfunction?: Mitochondrial transfer is a potential cure for many diseases but proof of efficacy and safety is still lacking.

Transplantation of functional mitochondria directly into defective cells is a novel approach that has recently caught the attention of scientists and the general public alike. Could this be too good to be true?

Mechanisms behind the Immunoregulatory Dialogue between Mesenchymal Stem Cells and Th17 Cells.

Mesenchymal stem cells (MSCs) exhibit potent immunoregulatory abilities by interacting with cells of the adaptive and innate immune system. In vitro, MSCs inhibit the differentiation of T cells into T helper 17 (Th17) cells and repress their proliferation. In vivo, the administration of MSCs to treat various experimental inflammatory and autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and bowel disease showed promising therapeutic results. These therapeutic properties mediated by MSCs are associated with an attenuated immune response characterized by a reduced frequency of Th17 cells and the generation of regulatory T cells. In this manuscript, we review how MSC and Th17 cells interact, communicate, and exchange information through different ways such as cell-to-cell contact, secretion of soluble factors, and organelle transfer. Moreover, we discuss the consequences of this dynamic dialogue between MSC and Th17 well described by their phenotypic and functional plasticity.

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response.

Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune-mediated diseases. They exert immunoregulatory and tissue-restoring effects. MSC-mediated transfer of mitochondria (MitoT) has been demonstrated to rescue target organs from tissue damage, yet the mechanism remains to be fully resolved. Therefore, we explored the effect of MitoT on lymphoid cells. Here, we describe dose-dependent MitoT from mitochondria-labeled MSCs mainly to CD4+ T cells, rather than CD8+ T cells or CD19+ B cells. Artificial transfer of isolated MSC-derived mitochondria increases the expression of mRNA transcripts involved in T-cell activation and T regulatory cell differentiation including FOXP3, IL2RA, CTLA4, and TGFβ1, leading to an increase in a highly suppressive CD25+ FoxP3+ population. In a GVHD mouse model, transplantation of MitoT-induced human T cells leads to significant improvement in survival and reduction in tissue damage and organ T CD4+ , CD8+ , and IFN-γ+ expressing cell infiltration. These findings point to a unique CD4+ T-cell reprogramming mechanism with pre-clinical proof-of-concept data that pave the way for the exploration of organelle-based therapies in immune diseases.

Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance.

The crosstalk between hematopoietic stem cells (HSC) and bone marrow (BM) microenvironment is critical for homeostasis and hematopoietic regeneration in response to blood formation emergencies after injury, and has been associated with leukemia transformation and progression. Intercellular signals by the BM stromal cells in the form of cell-bound or secreted factors, or by physical interaction, regulate HSC localization, maintenance, and differentiation within increasingly defined BM HSC niches. Gap junctions (GJ) are comprised of arrays of membrane embedded channels formed by connexin proteins, and control crucial signaling functions, including the transfer of ions, small metabolites, and organelles to adjacent cells which affect intracellular mechanisms of signaling and autophagy. This review will discuss the role of GJ in both normal and leukemic hematopoiesis, and highlight some of the most novel approaches that may improve the efficacy of cytotoxic drugs. Connexin GJ channels exert both cell-intrinsic and cell-extrinsic effects on HSC and BM stromal cells, involved in regenerative hematopoiesis after myelosuppression, and represent an alternative system of cell communication through a combination of electrical and metabolic coupling as well as organelle transfer in the HSC niche. GJ intercellular communication (GJIC) in the HSC niche improves cellular bioenergetics, and rejuvenates damaged recipient cells. Unfortunately, they can also support leukemia proliferation and survival by creating leukemic niches that provide GJIC dependent energy sources and facilitate chemoresistance and relapse. The emergence of new strategies to disrupt self-reinforcing malignant niches and intercellular organelle exchange in leukemic niches, while at the same time conserving normal hematopoietic GJIC function, could synergize the effect of chemotherapy drugs in eradicating minimal residual disease. An improved understanding of the molecular basis of connexin regulation in normal and leukemic hematopoiesis is warranted for the re-establishment of normal hematopoiesis after chemotherapy.

Abstract 1910: Regulation of ovarian tumor microenvironment dynamics by compressive stress

Abstract Ovarian cancer (OvCa) is the most fatal gynecologic malignancy and the fifth leading cause of overall cancer death among American women with a low (27%) 5-year survival rate, as 75% of women are diagnosed with disseminated intra-peritoneal (IP) metastasis. OvCa cells detach from the primary tumor and shed into the peritoneal cavity, adhere to the peritoneal mesothelial cell (MC) monolayer, intercalate within this layer, and invade into the submesothelial matrix, where they proliferate and form secondary lesions. More than one third of OvCa patients develop ascites that correlates with relapse and poor prognosis. The accumulated ascites can reach volumes up to 5 liters, causing a striking elevation in intraperitoneal pressure (IPP) from normally sub-atmospheric ~5 mmHg to as high as 27 mmHg, impacting the tumor microenvironment including host and tumor cells. The pressure created by accumulated ascites alters the force environment in the peritoneal cavity, causing strain and compressive forces on peritoneal structures. Yet, the mechanism through which ascites-induced IPP influences OvCa progression is poorly understood. The aim of this study is to understand how ascites-induced IPP promotes OvCa progression. To model the compressive force present in vivo due to accumulated tense ascites (~27 mmHg), we evaluated the effects of compressive force on primary human and murine MC monolayers and murine peritoneal explants using the Flexcell Compression System. Strikingly, compressed MC and peritoneal explants exhibited phenotypic alterations and formed abundant Tunneling Nanotubes (TNT), which are cell membrane extensions that modulate transfer of organelles between cells under stress. Furthermore, compression of OvCa cells adherent to murine peritoneal explants show intense formation of TNT between OvCa cells and peritoneal MC. Remarkably, TNT formed under compression displayed membrane distension and modulated the transfer of mitochondria from MC to OvCa cells. Moreover, collected peritoneal explants from OvCa murine model with intense ascites showed TNT formation and changes in the peritoneal sub-mesothelial collagen ultrastructure. This study reveals a novel response of OvCa cells and the tumor microenvironment to mechanical compression, uncovering a new mechanism by which OvCa metastatic success may be regulated. Note: This abstract was not presented at the meeting. Citation Format: Marwa Asem, Allison Young Young, Alejandro ClaureDeLaZerda, Matthew Ravosa, Sharon Stack. Regulation of ovarian tumor microenvironment dynamics by compressive stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1910.

PO200 Prevalence and Clinical Correlates of Blunted Heart Rate Dip In Chronic Kidney Disease: Findings From Ibadan Cardiovascular and Renal Event In People With Chronic Kidney Disease (CRECKID) Study

In the preceding chapter, we have discussed the barriers to therapeutics delivery and organelle transfer at the cellular level. Aging, however, is a systemic degenerative process. The availability of technologies for effective systemic delivery is a prerequisite for the successful development of biogerontological interventions. In this chapter, we will present the importance of systemic delivery to interventive biogerontology, and will also highlight the impediments to intervention administration at the organismal level.

Concise Review: Intercellular Communication Via Organelle Transfer in the Biology and Therapeutic Applications of Stem Cells.

The therapeutic potential of stem cell-based therapies may be largely dependent on the ability of stem cells to modulate host cells rather than on their differentiation into host tissues. Within the last decade, there has been considerable interest in the intercellular communication mediated by the transfer of cytoplasmic material and organelles between cells. Numerous studies have shown that mitochondria and lysosomes are transported between cells by various mechanisms, such as tunneling nanotubes, microvesicles, and cellular fusion. This review will focus on the known instances of organelle transfer between stem cells and differentiated cells, what effects it has on recipient cells and how organelle transfer is regulated. Stem Cells 2019;37:14-25.

Mesenchymal Stem Cells Shift Mitochondrial Dynamics and Enhance Oxidative Phosphorylation in Recipient Cells.

Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states.

Do microvesicles derived from adipose mesenchymal stem cells have a therapeutic potential on Escherichia coli lipopolysaccharides-induced sepsis in Zona fasciculata of adult male albino rats? A histological study

Introduction: Sepsis is a major health problem with high mortality rate, despite advanced medications. Although hypothalamic-pituitary-adrenal (HPA) axis activation can control its destructive inflammatory reactions, adrenal insufficiency (AI) is commonly associated with it. Mesenchymal Stem Cell-Derived Microvesicles (MSCs-MVs) were proved to be as effective as their origin cells in tissue repair.Aim of the work: To study the effects of Escherichia coli-lipopolysaccharides (E. coli-LPS) induced sepsis on Zona fasciculata of adult male albino rats and probable therapeutic effects of adipose derived mesenchymal stem cells-microvesicles (ADMSCs-MVs).Materials and Methods: Forty-four adult male albino rats were divided into three groups; (I) the controls, (II) LPS and (III) MV. Sepsis was induced in LPS and MV-groups using E. coli-LPS. Four hours later, MV-group received single intravenous (IV) injection of PKH26 labelled ADMSCs-MVs. All animals were sacrificed 48 hours after ADMSCs-MVs administration. Tumor necrosis factor-α (TNF-α), cyclo-oxygenase-2 (COX-2) and nitric oxide (NO) levels were measured in adrenal homogenates of each group. Sections from all groups were subjected to HE mostly through transfer of proteins, mRNA, microRNA and/or organelles with reparative functions from ADMSCs to the injured tissues.

Cellular mechanisms responsible for cell-to-cell spreading of prions.

Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrPSc). These abnormal aggregated PrPSc species multiply in infected cells by recruiting and converting the host PrPC protein into new PrPSc. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrPSc-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrPSc in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative diseases.

Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions.

Cell-to-cell communication is essential for the organization, coordination, and development of cellular networks and multi-cellular systems. Intercellular communication is mediated by soluble factors (including growth factors, neurotransmitters, and cytokines/chemokines), gap junctions, exosomes and recently described tunneling nanotubes (TNTs). It is unknown whether a combination of these communication mechanisms such as TNTs and gap junctions may be important, but further research is required. TNTs are long cytoplasmic bridges that enable long-range, directed communication between connected cells. The proposed functions of TNTs are diverse and not well understood but have been shown to include the cell-to-cell transfer of vesicles, organelles, electrical stimuli and small molecules. However, the exact role of TNTs and gap junctions for intercellular communication and their impact on disease is still uncertain and thus, the subject of much debate. The combined data from numerous laboratories indicate that some TNT mediate a long-range gap junctional communication to coordinate metabolism and signaling, in relation to infectious, genetic, metabolic, cancer, and age-related diseases. This review aims to describe the current knowledge, challenges and future perspectives to characterize and explore this new intercellular communication system and to design TNT-based therapeutic strategies.

The Role of Rho-GTPases and actin polymerization during Macrophage Tunneling Nanotube Biogenesis

Macrophage interactions with other cells, either locally or at distances, are imperative in both normal and pathological conditions. While soluble means of communication can transmit signals between different cells, it does not account for all long distance macrophage interactions. Recently described tunneling nanotubes (TNTs) are membranous channels that connect cells together and allow for transfer of signals, vesicles, and organelles. However, very little is known about the mechanism by which these structures are formed. Here we investigated the signaling pathways involved in TNT formation by macrophages using multiple imaging techniques including super-resolution microscopy (3D-SIM) and live-cell imaging including the use of FRET-based Rho GTPase biosensors. We found that formation of TNTs required the activity and differential localization of Cdc42 and Rac1. The downstream Rho GTPase effectors mediating actin polymerization through Arp2/3 nucleation, Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous 2 (WAVE2) proteins are also important, and both pathways act together during TNT biogenesis. Finally, TNT function as measured by transfer of cellular material between cells was reduced following depletion of a single factor demonstrating the importance of these factors in TNTs. Given that the characterization of TNT formation is still unclear in the field; this study provides new insights and would enhance the understanding of TNT formation towards investigating new markers.

Xenotransplantation of human mesenchymal stem cells alters host gene expression following prolonged high fat feeding

BackgroundInitially identified as plastic‐adherent cells, human mesenchymal stem cells (hMSCs) are non‐hematopoietic stem cells which are capable of differentiating into a multitude of cell lineages. Over the past decade the number of clinical trials involving hMSCs has steadily increased, resulting in hMSCs being the most commonly used cells in tissue engineering and regenerative medicine. Known to preferentially home to sites of injury and inflammation, administered hMSCs have exhibited promotion of host tissue repair through donor cell engraftment, release of cell signaling factors, and transfer of healthy organelles. As such, enhanced hMSC engraftment to host tissues and improved therapeutic potential may be induced by a state of low‐grade inflammation. Here we induce low‐grade inflammation through excessive nutrient consumption, achieved through prolonged high fat feeding.PurposeTo examine the impact of hMSC treatment on the liver tissue of mice following a prolonged high fat feeding regiment.MethodsAt 4 weeks of age, mice were placed on a high fat diet (60% kcal fat) for 20 weeks in order to elicit an obese phenotype. Following dietary manipulation, mice were randomly divided into two groups: hMSC treatment (HFM; n = 8) or saline control (HFS; n = 8). Mitochondrial metabolism, microarray gene expression profiling, and metabolomic profiling of host liver tissue were specifically highlighted for their important role in the obese phenotype.ResultsAs a measure of mitochondrial metabolic activity, maximal complex I oxygen consumption (supported by the addition of ADP) was higher in HFM animals (p<0.05). The marker of mitochondrial abundance, citrate synthase, was also elevated following hMSC administration (p<0.05). Microarray gene expression profiling identified 226 genes with significant differential expression between groups ‐ fold change (±1.2) and p‐value (<0.01). Specific gene networks and pathway analysis commonly identified cellular signalling and actin cytoskeleton regulation as upregulated processes in HFM mice (p<0.01).ConclusionsOur data indicate that xenogeneic hMSC treatment improves metabolic capacity of host liver and results in widespread host gene shifting. The upregulation of cell signaling and actin cytoskeleton regulation may provide mechanistic insight into how hMSCs impart their ability to migrate to areas of inflammation and transfer organelles to host tissues.Support or Funding InformationThis study was supported by NSERC (JS). This research was supported by PhD funding to CN from MitoCanada and Alberta Innovates – Health Solutions.