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Background Mesenchymal stem cell (MSC) therapy is an important alternative for GVHD treatment, but a third of patients fail to respond to such therapy. Therefore, strategies to enhance the immunosuppressive potential of MSCs constitute an active area of investigation. Here, we proposed an innovative priming strategy based on the plasma obtained from GVHD patients and tested whether this approach could enhance the immunosuppressive capacity of MSCs. Methods We obtained the plasma from healthy as well as acute (aGVHD) and chronic (cGVHD) GVHD donors. Plasma samples were characterized according to the TNF-α, IFN-γ, IL-10, IL-1β, IL-12p40, and IL-15 cytokine levels. The MSCs primed with such plasmas were investigated according to surface markers, morphology, proliferation, mRNA expression, and the capacity to control T cell proliferation and Treg generation. Results Interestingly, 57% of aGVHD and 33% of cGVHD plasmas significantly enhanced the immunosuppressive potential of MSCs. The most suppressive MSCs presented altered morphology, and those primed with cGHVD displayed a pronounced overexpression of ICAM-1 on their surface. Furthermore, we observed that the ratio of IFN-γ to IL-10 cytokine levels in the plasma used for MSC priming was significantly correlated with higher suppressive potential and Treg generation induction by primed MSCs, regardless of the clinical status of the donor. Conclusions This work constitutes an important proof of concept which demonstrates that it is possible to prime MSCs with biological material and also that the cytokine levels in the plasma may affect the MSC immunosuppressive potential, serving as the basis for the development of new therapeutic approaches for the treatment of immune diseases.

The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.

Objectives Melanoma is a type of skin cancer derived from melanocytes, with a high mortality rate and a poor prognosis. Interestingly, it has been demonstrated that melanoma patients present a spontaneous T-cell response against their tumor, but at a certain time, the immune response becomes ineffective. In this process, T cells are suppressed, favoring tumor escape and growth. In order to investigate whether the immune system itself could favor tumor evasion, we explored the potential of the secretome generated by melanoma to control T cell functions, considering the exposure of tumor cells to an inflammatory or non-inflammatory environment. Materials and methods Initially, PBMCs were isolated from healthy donors (n = 4) and cultured for 3 days in RPMI media (conditioned media – rCM) or in RPMI media supplemented with PHA (inflammatory-conditioned media – iCM). The melanoma lineage MEWO was expanded in RPMI until reaching 70% confluence, then some of them were treated with rCM, or iCM for 24 hours. On the last day of cultivation, RPMI, rCM, and iCM were removed, the cells were washed and cultured for 15 hours in RPMI medium without animal protein. The media were aliquoted and used as secretome from melanoma previously submitted to a control (RPMI), non-inflammatory (Sec), and inflammatory stimulus (iSec). Initially, we used CFSE dye to investigate by Flow Cytometry whether RPMI, Sec, and iSec exert any effects on T-cell proliferation. Also, we determined the expression of the activation markers HLA-II and CD69 on T-cells. Results and discussion Interestingly, we found that all the secretomes used were able to significantly control the proliferation of T cells, however, the most pronounced effect occurred in T cells treated with iSec. Corroborating this finding, T cells submitted to the iSec showed reduced expression of activation markers CD69 and HLA-II. Conclusion These findings show that although melanoma has a constitutive capacity to control T-cells function and escape from immune surveillance, the exposure of tumor cells to the inflammatory environment plays an important role in enabling these cells to perform a more potent immunosuppressive function.

Skin aging has been primarily related to aesthetics and beauty. Therefore, interventions have focused on reestablishing skin appearance, but not necessarily skin health, function, and resilience. Recently, cellular senescence was shown to play a role in age-related skin function deterioration and influence organismal health and, potentially, longevity. In the present study, a two-step screening was performed to identify peptides capable of reducing cellular senescence in human dermal fibroblasts (HDF) from Hutchinson-Gilford Progeria (HGPS) patients. From the top four peptides of the first round of screening, we built a 764-peptide library using amino acid scanning, of which the second screen led to the identification of peptide 14. Peptide 14 effectively decreased HDF senescence induced by HGPS, chronological aging, ultraviolet-B radiation, and etoposide treatment, without inducing significant cell death, and likely by modulating longevity and senescence pathways. We further validated the effectiveness of peptide 14 using human skin equivalents and skin biopsies, where peptide 14 promoted skin health and reduced senescent cell markers, as well as the biological age of samples, according to the Skin-Specific DNA methylation clock, MolClock. Topical application of peptide 14 outperformed Retinol treatment, the current gold-standard in “anti-aging” skin care. Finally, we determined that peptide 14 is safe for long-term applications and also significantly extends both the lifespan and healthspan of C. elegans worms tested in two independent testings. This highlights the potential for geroprotective applications of the senotherapeutic compounds identified using our screening platform beyond the skin.

Highlights • The SARS-CoV-2 and dengue syndemic is a reality in several countries worldwide. • Prior dengue infection did not impact clinical parameters of COVID-19 patients. • Active dengue fever worsened the pulmonary function of COVID-19 patients. • Active and prior dengue infection were associated with an increase in blood glucose levels., Originated in Wuhan, China, the coronavirus 19 disease (COVID-19) has quickly spread worldwide, reaching countries that already faced other endemics and epidemics. In Brazil, such a concerning situation includes arboviruses, among which the dengue virus stands out. Here, we determined the rate of SARS-CoV-2/dengue virus co-infection in a total of 178 patients with COVID-19 symtoms admitted into a large public hospital of the Federal District of Brazil. Furthermore, we evaluated whether prior or active dengue virus infection influenced hematological, biochemical, and clinical parameters of such patients. One hundred and twelve (63%) individuals tested positive for COVID-19, of which 43 (38.4%) were co-infected with dengue virus, and 50 (44.6%) had antibodies indicative of previous dengue infection. Co-infected patients showed lower numbers of circulating lymphocytes and monocytes, higher glucose rates, and a worse pulmonary condition. Of note, prior infections with dengue virus did not influence clinical parameters, but active dengue fever resulted in higher hospitalization rate. In conclusion, amid the current complex epidemiological scenario in Brazil, our data support the notion that SARS-CoV-2 and dengue co-infection affects an important percentage of COVID-19 patients and leads to worse clinical parameters, requiring greater attention from health authorities., Graphical abstract Image, graphical abstract

Trypanosoma cruzi is the etiological agent of Chagas Disease, which affects 6-7 million people worldwide. Since the early stages of infection and throughout its life cycle, the parasite is exposed to several genotoxic agents. Furthermore, DNA damage is also part of the mechanism of action of at least a few trypanocidal drugs, including Benznidazole. Thus, it is paramount for the parasite to count on an efficient DNA repair machinery to guarantee genome integrity and survival. The present work provides an up-to-date review of both the conserved and peculiar DNA repair mechanisms described in T. cruzi against oxidative stress, ultraviolet and ionizing radiation, DNA adduct-inducing agents, and Benznidazole. The comprehension of the DNA repair mechanisms of the parasite may shed light on the parasite evolution and possibly pave the way for the development of novel and more effective trypanocidal drugs.

Chagas disease (CD), caused by Trypanosoma cruzi, is the main parasitic disease in the Western Hemisphere, with an increasing number of cases, especially in non-endemic regions. The disease is characterized by cardiomegaly and mega viscera, nevertheless, the clinical outcome is hard to predict, underscoring the need for further research into the pathophysiology of CD. Even though most basic and translational research involving CD is performed using in vivo models, in vitro models arise as an ethical, rapidly evolving, and physiologically relevant alternative for CD research. In the present review, we discuss the past and recent in vitro models available to study the host-parasite interface in cardiac and intestinal CD, critically analyzing the possibilities and limitations of state-of-the-art alternatives for the CD host-parasite investigation.

The conservation of genomic integrity and stability is essential for cell survival. DNA Damage Responses (DDRs) are considered of paramount importance for all living beings and involve mechanisms of cell cycle regulation and damage-specific DNA repair pathways. Hydrogen peroxide (H2O2) is a compound that, in supraphysiological concentrations, damages biomolecules including the DNA, causing base modifications and strand breaks. There is evidence that Trypanosoma cruzi, the protozoan that causes Chagas disease, interferes in the host cell's DNA metabolism. In order to investigate the influence of T. cruzi infection over the host cell capacity to withstand and repair DNA damage, we analyzed L6 cells infected with Berenice, and Colombiana T. cruzi strains according to their viability, proliferation, morphology, DNA degradation, expression of DNA repair, and cell cycle genes following H2O2 treatment. It was noted that T. cruzi infection might act as either a stressor or a protective element of host DNA, depending on the strain and H2O2 concentration. Cells infected with Berenice strain and treated with 0.8 mM H2O2 presented a reduced DNA damage response intensity (e.g., BER and HR). Infection with T. cruzi Colombiana prevented the activation of DNA repair pathways in response to 0.8mM and 1.6mM H2O2 (NER and MMR). Nevertheless, since cellular viability was not significantly compromised in Colombiana-infected cells following the oxidative insult, it is possible that the parasite directly influenced the host DNA repair machinery. Our results support the notion that T. cruzi is able to modulate the host cell DNA metabolism in a strain-dependent manner, an event which can be explored in future drug development strategies.

Angiogenesis is implicated in the development of a variety of pathological processes, most commonly cancer. It is essential for tumor growth and metastasis, making it an important cancer therapeutic target. Naturally occurring substances have led to the discovery of anticancer agents. Flavokawain B (FKB), a chalcone isolated from the root extracts of kava-kava plant, inhibits proliferation and causes apoptosis in vitro and in vivo of various cancer cell lines. The antimetastatic potential of FKB has also been suggested. In our study, we confirm the antiangiogenic action of FKB in vitro and, for the first time, demonstrate its strong antiangiogenic activity in vivo, using a zebrafish model. Our data show that FKB inhibits human brain endothelial cell (HUVEC) migration and tube formation even at very low and non-toxic concentrations. Moreover, FKB blocks angiogenesis process in zebrafish, with a dramatic reduction of subintestinal vein formation in a dose-dependent manner. Flavokawain B at the concentration of 2.5 μg/mL did not exhibit any toxic effects in zebrafish larvae and caused a markedly or complete obliteration of subintestinal vein formation. Our findings along with previously published data confirm that FKB may form the basis for creating an additional tool in the treatment of cancer and other neovascularization-related diseases. Copyright © 2017 John Wiley & Sons, Ltd.

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi (T. cruzi), is the main parasitic disease in the Western Hemisphere. Unfortunately, its physiopathology is not completely understood, and cardiomegaly development is hard to predict. Trying to explain tissue lesion and the fact that only a percentage of the infected individuals develops clinical manifestations, a variety of mechanisms have been suggested as the provokers of CD, such as parasite persistence and autoimmune responses. However, holistic analysis of how parasite and host-related elements may connect to each other and influence clinical outcome are still scarce in the literature. Here, we investigated murine models of CD caused by three different pathogen strains: Colombian, CL Brener and Y strains, and employed parasitological and immunological tests to determine parasite load, antibody reactivity, and cytokine production during the acute and chronic phases of the disease. Also, we developed a quantitative PCR (qPCR) protocol to quantify T. cruzi kDNA minicircle integration into the mammalian host genome. Finally, we used a robust correlation analysis to interconnect parasite- and host-related factors over time. Higher parasite load in the heart and in the intestine was significantly associated with IgG raised against host cardiac proteins. Also, increased heart and bone marrow parasitism was associated with a more intense leukocyte infiltration. kDNA integration rates correlated to the levels of IgG antibodies reactive to host cardiac proteins and interferon production, both influencing tissue inflammation. In conclusion, our results shed light into how inflammatory process associates with parasite load, kDNA transfer to the host, autoreactive autoantibody production and cytokine profile. Altogether, our data support the proposal of an updated integrative theory regarding CD pathophysiology.

Mesenchymal Stem Cells (MSCs) have gained prominence as an important tool in cell therapy, especially considering their capacity to control the immune system. Due to this property, the application of MSCs has been investigated for the treatment of several immune disorders, such as diabetes, rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus, and graft-versus-host-disease (GvHD). The application of MSCs to treat inflammatory diseases has led to impressive results. However, individual response to treatment is still heterogeneous, and the number of cells required to treat humans is very high. The possibility of increasing the immunosuppressive potential of MSCs is seen at this point as a promising alternative to overcome such limitations. One of the most exploited strategies for this purpose has been the licensing of MSCs prior to clinical application. In this review, we will discuss the mechanisms by which MSCs modulate the immune response and the main advances in the licensing of these cells, with a special focus on the use of interferon gamma (IFN-γ). Also, we will address the main challenges ahead before licensed MSCs are finally used successfully in clinical practice.

Background Ovum pick-up (OPU) is a technique widely used for production of bovine embryos in-vitro. However, continuous OPU can be associated with the appearance of often irreversible ovarian lesions. The possibility of using stem cell therapy for treatment of infertility both in animals and in humans is currently under investigation, but the safety of intraovarian infusion of stem cells in bovines has not been established at this point. Therefore, in the present study we determined the feasibility and safety of intraovarian application of allogeneic MSC derived from adipose tissue of healthy cows. Methods Two OPU procedures were executed 15 days apart. Immediately following the second OPU, 2.5 million allogeneic MSCs were injected to the ovarian cortex of healthy nelore (n=5) and girolando (N=5) cows. The animals were subsequently evaluated by ultrasonography and clinical examination at 24, 48 and 72 hs post MSC injection. At 15, 30 and 45 days post MSC injection, new OPU procedures were executed and the number of viable oocytes collected, and rate of embryo production were determined. Results No clinical nor ultrasonographic alterations were detected in treated animals. Furthermore, similar numbers of viable oocytes, embryos produced, and rate of embryo production before and after MSC application were observed. Conclusion Based on these data, it can be concluded that the intra-ovarian application of 2.5 million adipose-derived MSC is safe. Future steps include the MSC treatment of individuals which present ovarian degeneration or lesions. Financial support This work was supported by CNPq, CAPES, FAPDF, FAPESP and Universidade of Brasilia.

The acquisition of complex karyotypes is related to the progression of chronic lymphocytic leukemia (CLL) and patients with this condition have a poor prognosis. Despite recent advances in the classification of prognosis in CLL patients, understanding of the molecular mechanisms that lead to genomic instability and progression of this disease remains inadequate. Interestingly, dysregulated expression of KDM4 members is involved in the progression of several cancer types and plays a role in the DNA damage response; however, the gene expression profile and the importance of KDM4 members in CLL are still unknown. Here, we assessed the gene expression profile of KDM4A, KDM4B, and KDM4C in 59 CLL samples and investigated whether these histone demethylases have any influence on the prognostic markers of this leukemia. KDM4A gene expression was higher in CLL patients as compared with control samples. In contrast, CLL samples showed decreased levels of the KDM4B transcript in relation to control cases, and no difference was detected in KDM4C expression. Furthermore, patients with positive expression of ZAP-70 had lower expression of KDM4B and KDM4C as compared with ZAP-70-negative patients. More importantly, patients with low expression of these histone demethylases had higher leukemic cell numbers and displayed adverse cytogenetic findings and the acquisition of a complex karyotype. The present data clearly show that the expression of KDM4 members is dysregulated in CLL and impact the prognosis of this leukemia. These findings are useful for a better understanding of the impact of epigenetics on CLL progression.

Background Heterodimeric methyltransferases GLP (EHMT1/KMT1D) and G9a (EHMT2/KMT1C) are two closely related enzymes that promote the monomethylation and dimethylation of histone H3 lysine 9. Dysregulation of their activity has been implicated in several types of human cancer. Patients and methods Here, in order to investigate whether GLP/G9a exerts any impact on Chronic Lymphocytic Leukemia (CLL), GLP/G9a expression levels were assessed in a cohort of 50 patients and the effects of their inhibition were verified for the viability of CLL cells. Also, qRT-PCR was used to investigate the transcriptional levels of GLP/G9a in CLL patients. In addition, patient samples were classified according to ZAP-70 protein expression by flow cytometry and according to karyotype integrity by cytogenetics analysis. Finally, a selective small molecule inhibitor for GLP/G9a was used to ascertain whether these methyltransferases influenced the viability of MEC-1 CLL cell lineage. Results mRNA analysis revealed that CLL samples had higher levels of GLP, but not G9a, when compared to non-leukemic controls. Interestingly, patients with unfavorable cytogenetics showed higher expression levels of GLP compared to patients with favorable karyotypes. More importantly, GLP/G9a inhibition markedly induced cell death in CLL cells. Conclusion Taken together, these results indicate that GLP is associated with a worse prognosis in CLL, and that the inhibition of GLP/G9a influences CLL cell viability. Altogether, the present data demonstrate that these methyltransferases can be potential markers for disease progression, as well as a promising epigenetic target for CLL treatment and the prevention of disease evolution.

This study aimed to evaluate the immunomodulatory and neuroprotective effects of allogeneic and cryopreserved mesenchymal stem cells (MSCs) on spinal cord injury. A total of 120 rats were distributed into the following groups: negative control (NC) - without injury, positive control (PC) - with injury without treatment, and group treated with MSC (GMSC) - with injury and treated. Motor function was evaluated by the BBB test at 24, 48, and 72 h and at 8 and 21 postoperative days. Spinal cords were evaluated by histopathology and immunohistochemistry to determine the expression of CD68, NeuN, and GFAP. IL-10, TNF-α, IL-1β, TGF-β, BDNF, GDNF, and VEGF expression was quantified by RT-PCR. The GMSC presented higher scores for motor function at 72 h and 8 and 21 days after injury, lower expression of CD68 at 8 days, and lower expression of GFAP at 21 days compared to the PC. In addition, higher expression of NeuN and lower degeneration of the white matter occurred at 21 days. The GMSC also showed higher expression of IL-10 24 h after injury, GDNF at 48 h and 8 days, and VEGF at 21 days. Moreover, lower expression of TNF-α was observed at 8 and 21 days and TGF-β at 24 h and 21 days. There were no differences in the expression of IL-1β and BDNF between the GMSC and PC. Thus, cryopreserved MSCs promote immunomodulatory and neuroprotective effects in rats with spinal cord injury by increasing IL-10, GDNF, and VEGF expression and reducing TNF-α and TGF-β expression.

The purpose of the study reported here was to develop and characterize microemulsions incorporating two ethanolic extracts of Brosimum gaudichaudii with different origins for topical application to treat the pigmentation disorder vitiligo. After plant extracts were obtained and submitted to in vitro biological assays against melanocytes, oil-in-water microemulsions incorporating the extracts were developed, characterized, and submitted to experiments to determine their stability, in vitro skin permeation, and irritant potential. The microemulsions were physically stable for at least 90 days and could incorporate the different concentrations of the furanocoumarins bergapten and psoralen from the Brosimum gaudichaudii extracts. Moreover, the microemulsions controlled the permeation of the furanocoumarins through the skin and were classified as weak irritants in a HET-CAM assay, which indicates their suitability for topical application. Although the extracts, by containing the furanocoumarins, stimulated melanocyte migration and pigmentation, their toxicity warrants caution. Nevertheless, because the findings suggest mechanisms by which the furanocoumarins can benefit the clinical treatment of vitiligo, microemulsions of them represent promising alternatives for topical application to treat the disorder.

Doxorubicin (Dox) is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiotoxicity. Evaluation of left ventricular function relies on measurements based on M-mode echocardiography. A new technique based on quantification of myocardial motion and deformation, strain echocardiography, has been showed promising profile for early detection of cardiac dysfunction. Different therapy strategies, such as flavonoid plant extracts and stem cells, have been investigated to improve heart function in toxic cardiomyopathy. This work aimed to assess early cardiac function improvement after treatments with either flavonoid extract from Camellia sinensis or mesenchymal stem cells in Dox cardiotoxicity using strain echocardiography. Twenty Wistar rats were randomly assigned to four groups. They received water (control, Dox, Dox + stem cells) or 100 mg/kg C. sinensis extract (Dox + C. sinensis) via gavage, daily, for four weeks. Animals also received saline (control) or 5 mg/kg doxorubicin (Dox, Dox + C. sinensis, Dox + stem cells) via intraperitoneal injection, weekly, for four weeks. Stem cells were injected (3 × 106 cells) through tail vein prior the beginning of the experiment (Dox + stem cells). Animals were evaluated by hematological, electrocardiography, echocardiography, and histopathological examinations. Dox cardiotoxicity was only diagnosed with strain echocardiography, detecting a decrease in ventricular function. C. sinensis extract did not prevent ventricular dysfunction induced by Dox. However, strain echocardiography examination revealed that Dox cardiotoxicity was significantly suppressed in rats treated with stem cells. In conclusion, strain echocardiography was able to detect precocity signs of heart failure and stem cell therapy showed cardioprotection effect against Dox cardiotoxicity.

Compression of spinal roots is an important medical problem, which may arise from intervertebral disc herniation, tumor growth or as a result of high energy accidents. Differently from avulsion, root crushing maintains the central/peripheral nervous system (CNS/PNS) connection, although the axons are axotomized and motoneurons degenerate. Such neuronal death may decrease and delay motor function recovery. In the present study we have investigated the neuroprotective effects of mesenchymal stem cell (MSC) therapy following such proximal lesions. Motor recovery and synaptic stabilization were analyzed by the use of morphological and functional approaches. For that, crushing the ventral roots at L4, L5 and L6 was unilaterally performed in Lewis rats. Four weeks after injury, an increased motoneuron survival was observed in the MSC-treated group, coupled with a smaller decrease of inputs at the motoneuron surface and nearby neuropil, seen by synaptophysin and synapsin immunolabeling and decreased astrogliosis, seen by GFAP immunolabeling. In this sense, MSC-treated group displayed a significant preservation of GABAergic terminals, indicating a possible neuroprotection to glutamate excitotoxicity. Motor function recovery was acutely improved in MSC-treated group as compared to Dulbeco's modified eagle medium (DMEM)-treated. Overall, we provide evidence that ventral root crushing (VRC), although milder than avulsion, results in significant loss of motoneurons (~51%) that can be reduced by MSC administration within the spinal cord. Such treatment also improves the number of synapses immunoreactive against molecules present in inhibitory inputs. Also, an increased number of regenerated axons was obtained in the MSC-treated group, in comparison to the DMEM-treated control. Overall, MSC therapy acutely improved limb strength and gait coordination, indicating a possible clinical application of such treatment following proximal lesions at the CNS/PNS interface.

In this study the time course of homing and the body distribution of systemically delivered bone marrow mesenchymal stem cells (BM-MSCs) after myocardial infarction (MI) were evaluated. BM-MSCs were isolated from Wistar rats, expanded in vitro, and their phenotypical characterization was performed by flow cytometer. Rats were randomly divided into three groups: control, sham MI, and MI. BM-MSCs (5 × 106) were labeled with 99mTc-HMPAO and injected through the tail vein 7 days after MI. Gamma camera imaging was performed at 5, 15, 30, and 60 min after cell inoculation. Due to the 99mTc short half-life, cell migration and location were also evaluated in heart sections using DAPI-labeled cells 7 days after transplantation. Phenotypical characterization showed that BM-MSCs were CD90+, CD73+, CD54+, and CD45-. Five minutes after 99mTc-HMPAO-labeled cell injection, they were detected in various tissues. The cells migrated mainly to the lungs (approximately 70%) and, in small amounts, to the heart, kidneys, spleen, and bladder. The number of cells in the heart and lungs decreased after 60 min. MI markedly increased the amount of cells in the heart, but not in the lungs, during the period of observation (4.55 ± 0.32 vs. 6.34 ± 0.67% of uptake in infarcted hearts). No significant differences were observed between control and sham groups. Additionally, 7 days after DAPI-labeled cells injection, they were still detected in the heart but only in infarcted areas. These results suggest that the migration of systemically delivered BM-MSCs to the heart is time dependent and MI specifically increases BM-MSCs homing to injured hearts. However, the systemic delivery is limited by cell entrapment in the lungs.