Use of mesenchymal stem cells to treat liver fibrosis:Current situation and future prospects

Progressive liver fibrosis is a major health issue for which no effective treatment is available,leading to cirrhosis and orthotopic liver transplantation.However,organ shortage is a reality.Hence,there is an urgent need to find alternative therapeutic strategies.Cellbased therapy using mesenchymal stem cells(MSCs) may represent an attractive therapeutic option,based ontheir immunomodulatory properties,their potential to differentiate into hepatocytes,allowing the replacement of damaged hepatocytes,their potential to promote residual hepatocytes regeneration and their capacity to inhibit hepatic stellate cell activation or induce their apoptosis,particularly via paracrine mechanisms.The current review will highlight recent findings regarding the input of MSC-based therapy for the treatment of liver fibrosis,from in vitro studies to pre-clinical and clinical trials.Several studies have shown the ability of MSCs to reduce liver fibrosis and improve liver function.However,despite these promising results,some limitations need to be considered.Future prospects will also be discussed in this review.     

Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation?

MSCs are multipotent cells that can be isolated from several human tissues and expanded ex vivo for clinical use. They comprise a heterogeneous population of cells, which, through production of growth factors, cell-to-cell interactions and secretion of matrix proteins, has a role in the regulation of hematopoiesis. In recent years, several experimental studies have shown that MSCs are endowed with immunomodulatory properties and with the capacity to promote graft survival in animal models. In view of these properties, MSCs have been tested in pilot studies aimed at preventing/treating graft rejection and at accelerating recovery after hematopoietic cell transplantation (HCT). The available clinical evidence deriving from these studies indicates that MSC infusion is safe and promising in terms of capacity of preventing graft failure. More debated is the effect of MSCs for what concerns their capacity of accelerating hematopoietic reconstitution after HCT. Whether the favorable effect of MSCs largely depends on the type of transplantation remains also a field of future investigation. Moreover, future researches should be oriented to gain more insights on MSC biological and functional mechanisms relevant for exploiting their use in the modulation of alloreactivity and in the promotion of hematopoietic reconstitution.     

MSC-based therapies in solid organ transplantation

Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169–1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107–111, 2013; Perico et al. in Transpl Int 26:867–878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412–422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.     

Assessment of human herpesvirus‐6 infection in mesenchymal stromal cells ex vivo expanded for clinical use

Abstract: Infection or reactivation of human herpesvirus (HHV)‐6 represents a potentially serious complication (often involving the central nervous system) in patients receiving either solid organ or hematopoietic stem cell transplantation. The objective of this study was to assess the risk of HHV‐6 infection/reactivation in mesenchymal stromal cells (MSCs). MSCs are multipotent cells displaying immunomodulatory properties that have been already successfully used in the clinical setting to enhance hematopoietic stem cell engraftment and to treat steroid‐refractory acute graft‐versus‐host disease. We analyzed 20 samples of ex vivo expanded MSCs, at different passages of culture, isolated both from bone marrow and from umbilical cord blood. Through Western blotting and immunocytochemistry techniques, we investigated the presence of the HHV‐6 receptor (CD46) on cell surface, whereas the presence of HHV‐6 DNA was evaluated by nested polymerase chain reaction assay. All of the MSC samples tested were positive for the virus receptor (CD46), suggesting their potential susceptibility to HHV‐6. However, none of the MSC samples derived from cultures, performed in the perspective of clinical use, was found to harbor HHV‐6. This preliminary observation on a consistent number of MSC samples, some of them tested at late in vitro passages, indicates a good safety profile of the product in terms of HHV‐6 contamination. Nevertheless, it remains important to set up in vitro experimental models to study MSCs' susceptibility to HHV‐6 (and HHV‐7) infection, to verify their capacity to integrate the virus into cellular DNA, and to investigate which experimental conditions are able to induce virus reactivation.     

Derivation and characterization of human fetal MSCs: An alternative cell source for large-scale production of cardioprotective microparticles

The therapeutic effects of mesenchymal stem cells (MSCs) transplantation are increasingly thought to be mediated by MSC secretion. We have previously demonstrated that human ESC-derived MSCs (hESC-MSCs) produce cardioprotective microparticles in pig model of myocardial ischemia/reperfusion (MI/R) injury. As the safety and availability of clinical grade human ESCs remain a concern, MSCs from fetal tissue sources were evaluated as alternatives. Here we derived five MSC cultures from limb, kidney and liver tissues of three first trimester aborted fetuses and like our previously described hESC-derived MSCs; they were highly expandable and had similar telomerase activities. Each line has the potential to generate at least 10^16–19 cells or 10^7–10 doses of cardioprotective secretion for a pig model of MI/R injury. Unlike previously described fetal MSCs, they did not express pluripotency-associated markers such as Oct4, Nanog or Tra1-60. They displayed a typical MSC surface antigen profile and differentiated into adipocytes, osteocytes and chondrocytes in vitro. Global gene expression analysis by microarray and qRT-PCR revealed a typical MSC gene expression profile that was highly correlated among the five fetal MSC cultures and with that of hESC-MSCs (r² > 0.90). Like hESC-MSCs, they produced secretion that was cardioprotective in a mouse model of MI/R injury. HPLC analysis of the secretion revealed the presence of a population of microparticles with a hydrodynamic radius of 50–65 nm. This purified population of microparticles was cardioprotective at ～1/10 dosage of the crude secretion.     

Adult Human Adipose Tissue Contains Several Types of Multipotent Cells

Multipotent mesenchymal stromal cells (MSCs) are a type of adult stem cells that can be easily isolated from various tissues and expanded in vitro. Many reports on their pluripotency and possible clinical applications have raised hopes and interest in MSCs. In an attempt to unify the terminology and the criteria to label a cell as MSC, in 2006 the International Society for Cellular Therapy (ISCT) proposed a standard set of rules to define the identity of these cells. However, MSCs are still extracted from different tissues, by diverse isolation protocols, are cultured and expanded in different media and conditions. All these variables may have profound effects on the selection of cell types and the composition of heterogeneous subpopulations, on the selective expansion of specific cell populations with totally different potentials and ergo, on the long-term fate of the cells upon in vitro culture. Therefore, specific molecular and cellular markers that identify MSCs subsets as well as standardization of expansion protocols for these cells are urgently needed. Here, we briefly discuss new useful markers and recent data supporting the rapidly emerging concept that many different types of progenitor cells are found in close association with blood vessels. This knowledge may promote the necessary technical improvements required to reduce variability and promote higher efficacy and safety when isolating and expanding these cells for therapeutic use. In the light of the discussed data, particularly the identification of new markers, and advances in the understanding of fundamental MSC biology, we also suggest a revision of the 2006 ISCT criteria.     

Mesenchymal stem cells for clinical application

Mesenchymal Stem Cells/Multipotent Marrow Stromal Cells (MSC) are multipotent adult stem cells present in all tissues, as part of the perivascular population. As multipotent cells, MSCs can differentiate into different tissues originating from mesoderm ranging from bone and cartilage, to cardiac muscle. Conflicting data show that MSCs could be pluripotent and able to differentiate into tissues and cells of non‐mesodermic origin as neurons or epithelial cells. Moreover, MSCs exhibit non‐HLA restricted immunosuppressive properties. This wide range of properties leads to increasing uses of MSC for immunomodulation or tissue repair. Based on their immunosuppressive properties MSC are used particularly in the treatment of graft versus host disease, For tissue repair, MSCs can work by different ways from cell replacement to paracrine effects through the release of cytokines and to regulation of immune/inflammatory responses. In regenerative medicine, trials are in progress or planed for healing/repair of different tissue or organs as bone, cartilage, vessels, myocardium, or epithelia. Although it has been demonstrated that ex‐vivo expansion processes using fetal bovine serum, recombinant growth factors (e.g. FGF2) or platelet lysate are feasible, definitive standards to produce clinical‐grade MSC are still lacking. MSCs have to be produced according GMP and regulation constraints. For answering to the numerous challenges in this fast developing field of biology and medicine, integrative networks linking together research teams, cell therapy laboratories and clinical teams are needed.     

Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat

Background

Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, uncertainty remains concerning the distribution, function, and fate of repopulating MSCs in recipient colonic tissues. Therefore, we investigated the role of transplanted MSCs in the repair phase of DSS colitis.

Methods

LacZ-labeled rat MSCs were transplanted into rats with colitis induced by 4% DSS on day 2. Regular water replaced the DSS solution on day 6. Therapeutic effect was evaluated on day 9 by clinicopathologic and growth factor/cytokine expression profiles. We analyzed the Notch signaling pathway by Western blotting and characterized immunofluorescence of lacZ-labeled MSCs with confocal laser microscopy. In vivo differentiation of MSC was confirmed by transmission electron microscopy (TEM).

Results

Recovery of colitis was modestly but significantly promoted by MSC transplantation due to proceeding cell cycle and inhibiting apoptosis in the epithelia. Tgfa mRNA expression increased significantly, while Notch signaling was inhibited in the colonic tissues with MSC transplantation. ??-Galactosidase-positive cells, which expressed ??-SMA, desmin, and vimentin, were infrequently detected in the lamina propria stroma. DSS exposure in vitro proved to be the most potent inducer for ??-SMA in MSCs where TEM demonstrated myogenic lineage differentiation.

Conclusions

We found that MSCs transplantation modestly promoted the repair of DSS colitis. The donor-derived MSCs were likely reprogrammed to differentiate to myogenic lineage cells by cues from the micro milieu. Further characterization of these cells is warranted as a basis for applying cell-based therapy for inflammatory bowel disease.     

Stem cells as potential novel therapeutic strategy for inflammatory bowel disease

Hematopoietic stem cell transplantation and mesenchymal stromal cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases. Hematopoietic stem cells (HSC) are thought to repopulate the immune system and reset the immunological response to luminal antigens. Mesenchymal stromal cells (MSC) are cells that have the capacity to differentiate into wide variety of distinct cell lineages and suppress immune responses in vitro and in vivo. Recent results from animal models and early human experience in graft-versus-host disease but also Crohn's Disease suggest that ex vivo expanded MSCs may have clinically useful immunomodulatory effects.     

Comprehensive characterization of mesenchymal stromal cells from patients with Fanconi anaemia

Fanconi anaemia (FA) is an inherited disorder characterized by pancytopenia, congenital malformations and a predisposition to develop malignancies. Alterations in the haematopoietic microenvironment of FA patients have been reported, but little is known regarding the components of their bone marrow (BM) stroma. We characterized mesenchymal stromal cells (MSCs) isolated from BM of 18 FA patients both before and after allogeneic haematopoietic stem cell transplantation (HSCT). Morphology, fibroblast colony‐forming unit (CFU‐F) ability, proliferative capacity, immunophenotype, differentiation potential, ability to support long‐term haematopoiesis and immunomodulatory properties of FA‐MSCs were analysed and compared with those of MSCs expanded from 15 age‐matched healthy donors (HD‐MSCs). FA‐MSCs were genetically characterized through conventional karyotyping, diepoxybutane‐test and array‐comparative genomic hybridization. FA‐MSCs generated before and after HSCT were compared. Morphology, immunophenotype, differentiation potential, ability in vitro to inhibit mitogen‐induced T‐cell proliferation and to support long‐term haematopoiesis did not differ between FA‐MSCs and HD‐MSCs. CFU‐F ability and proliferative capacity of FA‐MSCs isolated after HSCT were significantly lower than those of HD‐MSCs. FA‐MSCs reached senescence significantly earlier than HD‐MSCs and showed spontaneous chromosome fragility. Our findings indicate that FA‐MSCs are defective in their ability to survive in vitro and display spontaneous chromosome breakages; whether these defects are involved in pathophysiology of BM failure syndromes deserves further investigation.     

Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium

Most clinical studies have used autologous bone marrow (BM) stem cells for myocardial regeneration in elderly patients. We hypothesize that aging impairs the survival and differentiation potential of BM stem cells thus limiting their therapeutic efficacy. BM-derived MSCs from young (^YngMSCs; 8-12 weeks) and old (^OldMSCs; 24-26 months) rats were purified and assessed for their responsiveness to anoxia and reparability of infarcted heart. Higher expression of angiogenic growth factors was observed by ^YngMSCs under anoxia as compared to ^OldMSCs, cultured either alone or in co-culture (^Co-oldMSCs) with ^YngMSCs. Likewise, ^YngMSCs were more tolerant to apoptotic stimuli and showed higher ability to form tubular structures during in vitro Matrigel assay as compared to ^OldMSCs and ^Co-oldMSCs with a possible role of p21 and p27 as contributory survival factors. For in vivo studies, acute myocardial infarction model was developed in Fischer-344 rats (n = 38). The animals were grouped to receive 70 μl basal DMEM without cells (group 1) or containing 2 × 10^6YngMSCs (PKH67 labeled; group 2) or ^OldMSCs (PKH26 labeled; group 3) and mixture of ^YngMSCs + ^OldMSCs (1 × 10⁶ cells each; group 4). Histological studies revealed that by day 7, ^YngMSCs showed elongated morphology with orientation similar to the host muscle architecture. Electron microscopy and confocal imaging after fluorescent immunostaining showed superior angiomyogenic potential of ^YngMSCs. Echocardiography showed significantly preserved heart function indices in the animals transplanted with ^YngMSCs. Aging impairs the responsiveness of ^OldMSCs to anoxia and their differentiation potential. ^YngMSCs fail to alter the survival of ^OldMSCs under in vitro as well as in vivo conditions. It is therefore concluded that transplantation of stem cells from young donors would be a better option for heart cell therapy in future clinical studies.     

间充质干细胞的生物特性及其在冠心病治疗中的临床应用

间充质干细胞(m esenchym al stem cells,MSCs)是一些易于在体外扩增并且具有多种分化能力的原始细胞,它在适宜的环境中可以分化为骨、软骨、脂肪、纤维结缔组织、骨髓基质等不同细胞。已有大量试验研究MSCs的分离、纯化、培养,以及它的特性,并有临床前期的研究实验证实了MSCs对冠心病的治疗效果,现将上述国内外研究现况予以综述,并对尚未明确的相关问题进行探讨。     

间质干细胞在移植免疫中的研究进展

间质干细胞主要来源于骨髓,具有自我更新和多向分化潜能。近来发现间质干细胞具有低免疫原性和免疫调节作用,可影响T细胞、B细胞、自然杀伤细胞、抗原提呈细胞等免疫细胞功能,减轻器官移植后免疫排斥,有望在移植免疫领域得到广泛应用。本文就间质干细胞的免疫学特性,在移植免疫中的应用及可能的免疫调节机制作一综述。     

Drug Discovery Algorithm for Cutaneous Leishmaniasis

Cutaneous leishmaniasis is clinically widespread but lacks treatments that are effective and well tolerated. Because all present drugs have been grandfathered into clinical use, there are no examples of a pre-clinical product evaluation scheme that lead to new candidates for formal development. To provide oral agents for development targeting cutaneous leishmaniasis, we have implemented a discovery scheme that incorporates in vitro and in vivo testing of efficacy, toxicity, and pharmacokinetics/metabolism. Particular emphasis is placed on in vivo testing, progression from higher-throughput models to those with most clinical relevance, and efficient use of resources.     

MSCs分化为功能性肝细胞的研究进展

间充质干细胞(mesenchymal stemcells,MSCs)来源于中胚层间充质,广泛存在于骨髓、脐带组织、脐血、外周血、脂肪等组织中.在特定条件下,可以分化为骨、脂肪、神经细胞及肝细胞等多种细胞,进而作为一种替代器官移植的新的治疗方法.近年来,肝硬化等终末期肝病的发病率日益上升,成为影响人类健康的重大疾病之一.肝源紧张、免疫排斥限制了肝移植的临床应用,然而众多研究证实MSCs对肝纤维化、肝硬化等肝病的治疗作用可能与其分化为功能性肝细胞有关,但具体机制尚不十分清楚.本文就MSCs的分化能力及其分化的调控、分子机制和不同来源干细胞对肝纤维化的治疗作用作一综述.     

Transplantation of Mesenchymal Stem Cells Attenuates Acute Liver Failure in Mice via an Interleukin-4-dependent Switch to the M2 Macrophage Anti-inflammatory Phenotype

Background and AimsTransplantation of mesenchymal stem cells (MSCs) derived from bone marrow (BM) is an alternative treatment of acute liver failure (ALF) mainly because of the resulting anti-inflammatory activity. It is not known how MSCs regulate local immune responses and liver regeneration. This study explored the effects of MSCs on hepatic macrophages and the Wnt signaling pathway in ALF.MethodsMSCs were isolated from BM aspirates of C57BL/6J mice, and transplanted in mice with ALF induced by D-galactosamine (D-Gal). The proliferation of hepatocytes was assayed by immunohistochemical (IHC) staining of Ki-67 and proliferating cell nuclear antigen (PCNA). The levels of key proteins in the Wnt signaling pathway were assayed by western blotting and cytokines were determined enzyme-linked immunosorbent assays (ELISAs). A macrophage polarization assay characterized the M1/M2 ratio. The potential role of interleukin-4 (IL-4) in the biological activity of MSCs was determined by silencing of IL-4.ResultsTransplantation of allogeneic MSCs significantly attenuated D-Gal-induced hepatic inflammation and promoted liver regeneration. MSC transplantation significantly promoted a phenotypic switch from proinflamatory M1 macrophages to anti-inflammatory M2 macrophages, leading to significant Wnt-3a induction and activation of the Wnt signaling pathway in mice with D-Gal-induced ALF. Of the paracrine factors secreted by MSCs (G-CSF, IL-6, IL-1 beta, IL-4, and IL-17A), IL-4 was specifically induced following transplantation in the ALF model mice. The silencing of IL-4 significantly abrogated the phenotypic switch to M2 macrophages and the protective effects of MSCs in both the ALF model mice and a co-culture model in an IL-4 dependent manner.ConclusionsIn vivo and in vitro studies showed that MSCs ameliorated ALF through an IL-4-dependent macrophage switch toward the M2 anti-inflammatory phenotype. The findings may have clinical implications in that overexpression of IL-4 may enhance the therapeutic effects of allogeneic MSC transplantation in the treatment of ALF.     

Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells

Background

The clinical use of ex vivo-expanded T-regulatory cells for the treatment of T-cell-mediated diseases has gained increasing momentum. However, the recent demonstration that FOXP3⁺ T-regulatory cells may contain interleukin-17–producing cells and that they can convert into effector cells once transferred in vivo raises significant doubts about their safety. We previously showed that rapamycin permits the ex vivo expansion of FOXP3⁺ T-regulatory cells while impairing the proliferation of non-T-regulatory cells. Here we investigated the Th17-cell content and the in vivo stability of rapamycin-expanded T-regulatory cells as pertinent aspects of cell-based therapy.

Design and Methods

T-regulatory-enriched cells were isolated from healthy volunteers and were expanded ex vivo with rapamycin with a pre-clinical applicable protocol. T-regulatory cells cultured with and without rapamycin were compared for their regulatory activity, content of pro-inflammatory cells and stability.

Results

We found that CD4⁺CCR6⁺CD161⁺ T cells (i.e., precursor/committed Th17 cells) contaminate the T-regulatory cells cultured ex vivo in the absence of rapamycin. In addition, Th17 cells do not expand when rapamycin-treated T-regulatory cells are exposed to a “Th17-favorable” environment. Rapamycin-expanded T-regulatory cells maintain their in vitro regulatory phenotype even after in vivo transfer into immunodeficient NOD-SCID mice despite being exposed to the irradiation-induced pro-inflammatory environment. Importantly, no additional rapamycin treatment, either in vitro or in vivo, is required to keep their phenotype fixed.

Conclusions

These data demonstrate that rapamycin secures ex vivo-expanded human T-regulatory cells and provide additional justification for their clinical use in future cell therapy-based trials.     

Therapy with stem cells in inflammatory bowel disease

Inflammatory bowel disease(IBD) affects a part of the young population and has a strong impact upon quality of life. The underlying etiology is not known, and the existing treatments are not curative. Furthermore, a significant percentage of patients are refractory to therapy. In recent years there have been great advances in our knowledge of stem cells and their therapeutic applications. In this context, autologous hematopoietic stem cell transplantation(HSCT) has been used in application to severe refractory Crohn’s disease(CD), with encouraging results. Allogenic HSCT would correct the genetic defects of the immune system, but is currently not accepted for the treatment of IBD because of its considerable risks. Mesenchymal stem cells(MSCs) have immune regulatory and regenerative properties, and low immunogenicity(both autologous and allogenic MSCs). Based on these properties, MSCs have been used via the systemic route in IBD with promising results, though it is still too soon to draw firm conclusions. Their local administration in perianal CD is the field where most progress has been made in recent years, with encouraging results. The next few years will be decisive for defining the role of such therapy in the management of IBD.     

Lateral root morphogenesis is dependent on the mechanical properties of the overlaying tissues

In Arabidopsis, lateral root primordia (LRPs) originate from pericycle cells located deep within the parental root and have to emerge through endodermal, cortical, and epidermal tissues. These overlaying tissues place biomechanical constraints on the LRPs that are likely to impact their morphogenesis. This study probes the interplay between the patterns of cell division, organ shape, and overlaying tissues on LRP morphogenesis by exploiting recent advances in live plant cell imaging and image analysis. Our 3D/4D image analysis revealed that early stage LRPs exhibit tangential divisions that create a ring of cells corralling a population of rapidly dividing cells at its center. The patterns of division in the latter population of cells during LRP morphogenesis are not stereotypical. In contrast, statistical analysis demonstrated that the shape of new LRPs is highly conserved. We tested the relative importance of cell division pattern versus overlaying tissues on LRP morphogenesis using mutant and transgenic approaches. The double mutant aurora1 (aur1) aur2 disrupts the pattern of LRP cell divisions and impacts its growth dynamics, yet the new organ’s dome shape remains normal. In contrast, manipulating the properties of overlaying tissues disrupted LRP morphogenesis. We conclude that the interaction with overlaying tissues, rather than the precise pattern of divisions, is most important for LRP morphogenesis and optimizes the process of lateral root emergence.     

Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model

Aims/hypothesis

Islet transplantation is used therapeutically in a minority of patients with type 1 diabetes. Successful outcomes are hampered by early islet beta cell loss. The adjuvant co-transplantation of mesenchymal stromal cells (MSCs) has the promise to improve islet transplant outcome.

Methods

We used a syngeneic marginal islet mass transplantation model in a mouse model of diabetes. Mice received islets or islets plus 250,000 MSCs. Kidney subcapsule, intra-hepatic and intra-ocular islet transplantation sites were used. Apoptosis, vascularisation, beta cell proliferation, MSC differentiation and laminin levels were determined by immunohistochemical analysis and image quantification post-transplant.

Results

Glucose homeostasis after the transplantation of syngeneic islets was improved by the co-transplantation of MSCs together with islets under the kidney capsule (p?=?0.01) and by intravenous infusion of MSCs after intra-hepatic islet transplantation (p?=?0.05). MSC co-transplantation resulted in reduced islet apoptosis, with reduced numbers of islet cells positive for cleaved caspase 3 being observed 14 days post-transplant. In kidney subcapsule, but not in intra-ocular islet transplant models, we observed increased re-vascularisation rates, but not increased blood vessel density in and around islets co-transplanted with MSCs compared with islets that were transplanted alone. Co-transplantation of MSCs did not increase beta cell proliferation, extracellular matrix protein laminin production or alpha cell numbers, and there was negligible MSC transdifferentiation into beta cells.

Conclusions/interpretation

Co-transplantation of MSCs may lead to improved islet function and survival in the early post-transplantation period in humans receiving islet transplantation.