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Introduction/aims: Many small-sized, single-center preclinical studies have investigated the benefits of introducing stem cells into the interior of nerve conduit. The aims of this meta-analysis are to review and contrast the effects of various types of stem cells in in vivo models used to reconstruct peripheral nerve injuries (PNIs) and to assess the reliability and stability of the available evidence., Methods: A systematic search was conducted using Cochrane Library, Embase, PubMed, and Web of Science to identify studies conducted from January 1, 2000, to September 21, 2022, and investigate stem cell therapy in peripheral nerve reconstruction animal models. Studies that met the relevant criteria were deemed eligible for this meta-analysis., Results: Fifty-five preclinical studies with a total of 1234 animals were incorporated. Stem cells demonstrated a positive impact on peripheral nerve regeneration at different follow-up times in the forest plots of five outcome indicators: compound muscle action potential (CMAP) amplitude, latency, muscle mass ratio, nerve conduction velocity, and sciatic functional index (SFI). In most comparisons, stem cell groups showed substantial differences compared with the control groups. The superior performance of adipose-derived stem cells (ADSCs) in terms of SFI, CMAP amplitude, and latency (p < .001) was identified., Discussion: The findings consistently demonstrated a favorable outcome in the reconstruction process when utilizing different groups of stem cells, as opposed to control groups where stem cells were not employed., (© 2023 Wiley Periodicals LLC.)

Introduction: Nestin-expressing cells isolated from different human tissues reveal self-renewal capacity and a multilineage differentiation potential. In particular, adult stem/progenitor cell populations from exocrine glands such as the pancreas, salivary gland and sweat gland are characterized by prominent nestin expression. Interestingly, human mammary gland histological examinations also demonstrated the existence of nestin-positive cells in the ductal compartments. Within the scope of our previous work we wonder whether an isolation of nestin-positive cell populations from human mammary gland biopsies is possible and what characteristics they have in vitro. Cell populations from both sexes were propagated and subjected to a comparison with other gland-derived cell populations., Methods: Human mammary tissue biopsies were mechanically and enzymatically treated, and the isolated acini structures were observed with time-lapse microscopy to track adherently outgrowing cells. The proliferation potential of the cell population was assessed by performing growth curves. On the gene and protein levels we investigated the expression of stem cell markers as well as markers indicating multilineage differentiation., Results: We succeeded in establishing proliferating cell populations from breast tissue biopsies of both sexes. Our results display several similarities to the glandular stem cell populations from other exocrine glands. Beside their proliferation capacity during in vitro culture, the obtained cell populations are characterized by their prominent nestin expression. The cells share surface proteins commonly expressed on adult stem cells. We demonstrated the expression of stem cell-related genes like Oct4, Sox2, KLF4 and Nanog, and confirmed multipotent differentiation capacity by detecting transcripts expressed in endodermal, mesodermal and ectodermal cell types., Conclusion: With this study we present an efficient procedure for isolation and propagation of nestin-positive stem cells obtained from male and female breast tissue, which is frequently available. The established multipotent cell populations could be easily expanded in vitro and thus hold promise for cell-based therapies and personalized medicine.

Some cancers have a poor prognosis and often lead to local recurrence because they are resistant to available treatments, e.g., glioblastoma. Attempts have been made to increase the sensitivity of resistant tumors by targeting pathways involved in the resistance and combining it, for example, with radiotherapy (RT). We have previously reported that treating glioblastoma stem cells with an Nrf2 inhibitor increases their radiosensitivity. Unfortunately, the application of drugs can also affect normal cells. In the present study, we aim to investigate the role of the Nrf2 pathway in the survival and differentiation of normal human adipose-derived stem cells (ADSCs) exposed to radiation. We treated ADSCs with an Nrf2 inhibitor and then exposed them to X-rays, protons or carbon ions. All three radiation qualities are used to treat cancer. The survival and differentiation abilities of the surviving ADSCs were studied. We found that the enhancing effect of Nrf2 inhibition on cell survival levels was radiation-quality-dependent (X-rays > proton > carbon ions). Furthermore, our results indicate that Nrf2 inhibition reduces stem cell differentiation by 35% and 28% for adipogenesis and osteogenesis, respectively, using all applied radiation qualities. Interestingly, the results show that the cells that survive proton and carbon ion irradiations have an increased ability, compared with X-rays, to differentiate into osteogenesis and adipogenesis lineages. Therefore, we can conclude that the use of carbon ions or protons can affect the stemness of irradiated ADSCs at lower levels than X-rays and is thus more beneficial for long-time cancer survivors, such as pediatric patients. [ABSTRACT FROM AUTHOR]

Background: Nerve guide conduits are a promising strategy for reconstructing peripheral nerve defects. Improving the survival rate of seed cells in nerve conduits is still a challenge and microcarriers are an excellent three-dimensional (3D) culture scaffold. Here, we investigate the effect of the 3D culture of microcarriers on the biological characteristics of adipose mesenchymal stem cells (ADSCs) and to evaluate the efficacy of chitosan nerve conduits filled with microcarriers loaded with ADSCs in repairing nerve defects. Methods: In vitro, we prepared porous chitosan microspheres by a modified emulsion cross-linking method for loading ADSCs and evaluated the growth status and function of ADSCs. In vivo, ADSCs-loaded microcarriers were injected into chitosan nerve conduits to repair a 12 mm sciatic nerve defect in rats. Results: Compared to the conventional two-dimensional (2D) culture, the prepared microcarriers were more conducive to the proliferation, migration, and secretion of trophic factors of ADSCs. In addition, gait analysis, neuro-electrophysiology, and histological evaluation of nerves and muscles showed that the ADSC microcarrier-loaded nerve conduits were more effective in improving nerve regeneration. Conclusions: The ADSCs-loaded chitosan porous microcarrier prepared in this study has a high cell engraftment rate and good potential for peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Cell-therapy-based nerve repair strategies hold great promise. In the field, there is an extensive amount of evidence for better regenerative outcomes when using tissue-engineered nerve grafts for bridging severe gap injuries. Although a massive number of studies have been performed using rodents, only a limited number involving nerve injury models of large animals were reported. Nerve injury models mirroring the human nerve size and injury complexity are crucial to direct the further clinical development of advanced therapeutic interventions. Thus, there is a great need for the advancement of research using large animals, which will closely reflect human nerve repair outcomes. Within this context, this review highlights various stem cell-based nerve repair strategies involving large animal models such as pigs, rabbits, dogs, and monkeys, with an emphasis on the limitations and strengths of therapeutic strategy and outcome measurements. Finally, future directions in the field of nerve repair are discussed. Thus, the present review provides valuable knowledge, as well as the current state of information and insights into nerve repair strategies using cell therapies in large animals. [ABSTRACT FROM AUTHOR]

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Breastmilk is a dynamic, multi-faceted, and complex fluid containing a plethora of biochemical and cellular components that execute developmental effects or differentiation program, providing nourishment and immunity to newborns. Recently, it was reported that breastmilk contains a heterogeneous population of naïve cells, including pluripotent stem cells, multipotent stem cells, immune cells, and non-immune cells. The stem cells derived from breastmilk possess immune privilege and non-tumorigenic properties. Thus, breastmilk may represent an ideal source of stem cells collected by non-perceive procedure than other available sources. Thus, this "maternally originating natural regenerative medicine" may have innumerable applications in clinical biology, cosmetics, and pharmacokinetics. This review describes the efficient integrated cellular system of mammary glands, the impressive stem cell hierarchy of breastmilk, and their possible implications in translational research and therapeutics. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is one of the most frequent and troublesome complications of diabetes mellitus. Evidence from diabetic animal models and diabetic patients suggests that reduced availability of neuroprotective and pro-angiogenic factors in the nerves in combination with a chronic pro-inflammatory microenvironment and high level of oxidative stress, contribute to the pathogenesis of DN. Mesenchymal stem cells (MSCs) are of great interest as therapeutic agents for regenerative purposes, since they can secrete a broad range of cytoprotective and anti-inflammatory factors. Therefore, the use of the MSC secretome may represent a promising approach for DN treatment. Recent data indicate that the paracrine potential of MSCs could be boosted by preconditioning these cells with an environmental or pharmacological stimulus, enhancing their therapeutic efficacy. In the present study, we observed that the preconditioning of human adipose tissue-derived MSCs (AD-MSCs) with 150μM or 400μM of the iron chelator deferoxamine (DFX) for 48 hours, increased the abundance of the hypoxia inducible factor 1 alpha (HIF-1α) in a concentration dependent manner, without affecting MSC morphology and survival. Activation of HIF-1α led to the up-regulation of the mRNA levels of pro-angiogenic factors like vascular endothelial growth factor alpha and angiopoietin 1. Furthermore this preconditioning increased the expression of potent neuroprotective factors, including nerve growth factor, glial cell-derived neurotrophic factor and neurotrophin-3, and cytokines with anti-inflammatory activity like IL4 and IL5. Additionally, we observed that these molecules, which could also be used as therapeutics, were also increased in the secretome of MSCs preconditioned with DFX compared to the secretome obtained from non-preconditioned cells. Moreover, DFX preconditioning significantly increased the total antioxidant capacity of the MSC secretome and they showed neuroprotective effects when evaluated in an in vitro model of DN. Altogether, our findings suggest that DFX preconditioning of AD-MSCs improves their therapeutic potential and should be considered as a potential strategy for the generation of new alternatives for DN treatment. [ABSTRACT FROM AUTHOR]

Background: Transverse rectus abdominis musculocutaneous (TRAM) flap is one of the options in reconstruction after breast cancer surgery for breast reconstruction. Tissue necrosis often occurs in the third and fourth perfusion zones of the flap. A study was planned to find out the effects of adipose stromal vascular fraction (SVF) cells on viability of TRAM flap and the experimental model was designed to be applicable in clinical practice.Methods: Right inferior epigastric artery pedicled, 5 × 2.5 cm sized TRAM flap was used as a flap model in 30 rats in three groups (group 1: sham; group 2: phosphate-buffered saline (PBS); group 3: SVF cell injected). The viability of the flaps were assessed on the postoperative 7th day with photographs and software for the calculations.Results: The mean viable flap percentage to total flap area was recorded as 51.8% ± 11.19, 49.5% ± 10.30, 82.3% ± 9.56, in group 1, group 2, and group 3, respectively (p < 0.05). The mean capillary density was noted as 5.15 ± 0.56, 4.37 ± 0.58, and 12.40 ± 1.17 in groups 1, 2, and 3, respectively (p < 0.05). The fibrosis gradient indicated no difference between the groups (p > 0.05). Thein-vivodifferentiation of SVF cells to endothelial cells was noted. The blood VEGF levels showed a marked increase in the experimental group (p < 0.05).Conclusion: The adipose SVF cells were found out to improve the TRAM flap viability and decrease necrosis, especially in zone 3 and 4. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to show the efficacy of olfactory stem cells for injured facial nerve reconstruction in a rat model. Methods Olfactory stem cells were isolated from the olfactory mucosa of human participants. A 2-mm excision was performed on the right facial nerve of all rats. Reconstruction was performed with a conduit in group 1 ( n = 9); a conduit and phosphate-buffered saline in group 2 ( n = 9); and a conduit and labeled olfactory stem cell in group 3 ( n = 9). Rats were followed for whisker movements and electroneuronography (ENoG) analyses. Results The whisker-movement scores for group 3 were significantly different from other groups ( p < .001). ENoG showed that the amplitude values for group 3 were significantly different from group 1 and group 2 ( p = .030; p < .001). Group 3 showed marked olfactory stem cell under a fluorescence microscope. Conclusion This study suggests that olfactory stem cells may be used as a potent cellular therapy for accelerating the regeneration of peripheral nerve injuries. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2011-E2020, 2016 [ABSTRACT FROM AUTHOR]

Emerging bioreactor technologies offer an effective way for scaled-up production of large numbers of cells for cell therapy applications. One of the clinical paradigms where cell therapy can be an asset is restorative neurosciences. Nerve repair can benefit from the injections of stem cells and/or Schwann cells, acting as a source for axon myelination, myelin debris clearance, and trophic support. We have adapted microcarrier-based suspension bioreactor culture for Schwann cells (SCs) differentiated from a new stem cell source - skin-derived precursors (SKPs). SKPderived SCs attach and grow on different types of microcarriers in both static and stirred culture, with Cytodex 3 and CultiSpher-S found most effective. Inter-microcarrier migration of SKP-SCs represents a key mechanism for rapid expansion and colonization in stirred suspension culture. We have shown that microcarrierexpanded SKP-SCs cells express Schwann cell markers p75-NTR, GFAP and S100 and retain their key ability to myelinate axons both in vitro and in vivo. Scaled-up microcarrier-based production of SKP-SCs in suspension bioreactors appears feasible for timely generation of sufficient cell numbers for nerve repair strategies. [ABSTRACT FROM AUTHOR]

As a promising alternative to autologous nerve grafts, tissue-engineered nerve grafts have been extensively studied as a way to bridge peripheral nerve defects and guide nerve regeneration. The main difference between autogenous nerve grafts and tissue-engineered nerve grafts is the regenerative microenvironment formed by the grafts. If an appropriate regenerative microenvironment is provided, the repair of a peripheral nerve is feasible. In this study, to mimic the body’s natural regenerative microenvironment closely, we co-cultured Schwann cells (SCs) and adipose-derived stem cells (ADSCs) as seed cells and introduced them into a silk fibroin (SF)/collagen scaffold to construct a tissue-engineered nerve conduit (TENC). Twelve weeks after the three different grafts (plain SF/collagen scaffold, TENC, and autograft) were transplanted to bridge 1-cm long sciatic nerve defects in rats, a series of electrophysiological examinations and morphological analyses were performed to evaluate the effect of the tissue-engineered nerve grafts on peripheral nerve regeneration. The regenerative outcomes showed that the effect of treatment with TENCs was similar to that with autologous nerve grafts but superior to that with plain SF/collagen scaffolds. Meanwhile, no experimental animals had inflammation around the grafts. Based on this evidence, our findings suggest that the TENC we developed could improve the regenerative microenvironment and accelerate nerve regeneration compared to plain SF/collagen and may serve as a promising strategy for peripheral nerve repair. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The regrowth of amputated appendage extremities and the distal tips of digits represent models of tissue regeneration in multiple vertebrate taxa. In humans, digit tip injuries, including traumatic amputation and crush injuries, are among the most common type of injury to the human hand. Despite clinical reports demonstrating natural regeneration of appendages in lower vertebrates and human digits, current treatment options are suboptimal, and are complicated by the anatomical complexities and functions of the different tissues within the digits. Results: In light of these challenges, we focus on recent advancements in understanding appendage regeneration from model organisms. We pay special attention to the cellular programs underlying appendage regeneration, where cumulative data from salamanders, fish, frogs, and mice indicate that regeneration occurs by the actions of lineage-restricted precursors. We focus on pathologic states and the interdependency that exists, in both humans and animal models, between the nail organ and the peripheral nerves for successful regeneration. Conclusions: The increased understanding of regeneration in animal models may open new opportunities for basic and translational research aimed at understanding the mechanisms that support limb regeneration, as well as amelioration of limb abnormalities and pathologies. Developmental Dynamics 244:641-650, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across 'gaps' in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration. [ABSTRACT FROM AUTHOR]

Background/Aims: The treatment of peripheral nerve lesions still represents a clinical challenge. Several approaches such as novel biomaterials for nerve guides, addition of growth factors or cellular supplements moved in the focus of research. Especially the application of autologous stem cells is highly promising for future applications. Human sweat gland derived stem cells (hSGSCs) represent an easy accessible source of autologous adult stem cells and did already show a beneficial effect in dermal wound healing. Methods: In this study, the effect of hSGSCs on neurite outgrowth of primary adult or prenatal Dorsal root ganglia (DRG) neurons was analysed in an indirect co-culture model. Additionally, direct co-cultures with hSGSCs as a feeder layer were performed. Results: Adult and prenatal DRG neurons showed increased neurite outgrowth after 24 h co-culture with hSGSCs. The outgrowth increased significantly by the factors 5.6 and 2.6 respectively. Direct co-cultures revealed neurite alignment along the hSGSCs orientation. Conclusion: The paracrine influence of hSGSCs on neurite outgrowth, but also their ability to operate as a feeder layer with guidance properties shows great potential for future applications in peripheral nerve regeneration. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The strong rationale for cell-based therapy in multiple sclerosis is based on the ability of stem and precursor cells of neural and mesenchymal origin to attenuate neuroinflammation, to facilitate endogenous repair processes, and to participate directly in remyelination, if directed towards a myelin-forming fate. However, there are still major gaps in knowledge regarding induction of repair in chronic multiple sclerosis lesions, and whether transplanted cells can overcome the multiple environmental inhibitory factors which underlie the failure of endogenous repair. Major challenges in clinical translation include the determination of the optimal cellular platform, the route of cell delivery, and candidate patients for treatment. [ABSTRACT FROM AUTHOR]

Patients with peripheral nerve injuries face unpredictable and often suboptimal functional outcome, even following standard microsurgical nerve repair. The challenge of improving such outcomes following nerve surgical procedures has interested many research teams, in both clinical and fundamental fields. Some innovative treatments are presently being applied to a widening range of patients, whereas others will require further development before translation to human subjects. This article presents several recent advances in emerging therapies at various stages of clinical application. Nerve transfers have been successfully used in clinical settings, but new indications are being described, enlarging the range of patients who might benefit from them. Brief direct nerve electrical stimulation has been shown to improve nerve regeneration and outcome in animal models and in a small cohort of patients. Further clinical trials are warranted to prove the efficacy of this exciting and easily applicable approach. Animal studies also suggest a tremendous potential for stem and precursor cell therapy. Further studies will lead to a better understanding of their mechanisms of action in nerve repair and potential applications for human patients. [ABSTRACT FROM AUTHOR]

Objective(s) Bone marrow is the traditional source of human multipotent mesenchymal stem cells (MSCs), but adipose tissue appears to be an alternative and more readily available source. In this study, rat adipose-derived stem cells (ADSCs) were induced to differentiate into Schwann-like cells and compared with rat bone marrow stem cells (BMSCs) for their Schwann-like cells differentiation potential. Materials and Methods BMSCs and ADSCs were characterized for expression of MSCs-specific markers, osteogenic and adipogenic differentiation. They were induced to differentiate into Schwann-like cells and analyzed for expression of the Schwann specific markers. The immunocytochemical differentiation markers were S-100 and real time quantitative Real-time polymerase chain reaction (RT-PCR) markers were S100, P75 and glial fibrillary acidic protein (GFAP). 3-(4, 5-Dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Annexin V-Fluorescein isothiocyanate (FITC)/ Propidium iodide (PI) double labeling method were employed to detect early stage cell apoptosis. Results BMSCs and ADSCs showed similarities in expression of the MSC-specific markers, osteogenic and adipogenic differentiation. Both quantitative RT-PCR and immunocytochemical analysis demonstrated that BMSCs and ADSCs had equal expression of the Schwann-specific markers following Schwann-like cells differentiation. However, gene expression of P75 was higher in BMSCs compared with ADSCs. MTT assay and flow cytometry found that of the total BMSCs and ADSCs in the culture medium, 20% to 30% of the cells died, but the remaining cell population remained strongly attached to the substrate and differentiated. Conclusion Comparative analysis showed that Schwann-like cell differentiation potential of ADSCs was slightly decreased in comparison with BMSCs. Therefore, BMSCs are more favorable choice than ADSCs for tissue engineering. [ABSTRACT FROM AUTHOR]

Adult stem cells have therapeutic potential because of their intrinsic capacity for self-renewal, especially for bone regeneration. The present study shows the utility of ex vivo modified mesenchymal stem cells (MSC) to enhance bone density in an immunocompetent mouse model of osteopenia. MSC were transduced ex vivo with a recombinant adeno-associated virus 2 (rAAV2) expressing bone morphogenetic protein 2 (BMP2) under the transcriptional control of collagen type-1α promoter. To enrich bone homing in vivo, we further modified the cells to transiently express the mouse α4 integrin. The modified MSC were systemically administered to ovariectomized, female C57BL/6 mice. Effects of the therapy were determined by dual-energy X-ray absorptiometry, 3D micro-CT, histology and immunohistochemistry for up to 6 months. Results indicated that mice transplanted with MSC expressing BMP2 showed significant increase in bone mineral density and bone mineral content (P<0.001) with relatively better proliferative capabilities of bone marrow stromal cells and higher osteocompetent pool of cells compared to control animals. Micro-CT analysis of femora and other bone histomorphometric analyses indicated more trabecular bone following MSC-BMP2 therapy. Results obtained by transplanting genetically modified MSC from green fluorescent protein transgenic mouse suggested that production of BMP2 from transplanted MSC also influenced the mobilization of endogenous progenitors for new bone formation. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stem cells derived from bone marrow and adipose tissue are being considered for use in neural repair because they can differentiate after appropriate induction in culture into neurons and glia. The question we asked was if neurospheres could be harvested from adipose-derived stem cells and if they then could differentiate in culture to peripheral glial-like cells. Here, we demonstrate that adipose-derived mesenchymal stem cells can form nestin-positive non-adherent neurosphere cellular aggregates when cultured with basic fibroblast growth factor and epidermal growth factor. Dissociation of these neurospheres and removal of mitogens results in expression of the characteristic Schwann cell markers S100 and p75 nerve growth factor receptor and GFAP. The simultaneous expression of these glia markers are characteristic features of Schwann cells and olfactory ensheathing cells which have unique properties regarding remyelination and enhancement of axonal regeneration. When co-cultured with dorsal root ganglion neurons, the peripheral glial-like cells derived from adipose mesenchymal stem cells aligned with neuritis and stimulated neuritic outgrowth. These results indicate that neurospheres can be generated from adipose-derived mesenchymal stem cells, and upon mitogen withdrawal can differentiate into peripheral glial cells with neurotrophic effects. [Copyright &y& Elsevier]

Objective: Despite the capacity for spontaneous axonal regeneration, recovery after severe peripheral nerve injury remains variable and often very poor. In addition, autologous nerve grafts, considered to be the 'gold standard' in nerve repair technique, are plagued by restricted donor tissue availability and donor site morbidity. Our primary objective is to highlight new and emerging methods of nerve repair, which have the potential to significantly improve both the functional and behavioral outcome after clinical nerve injury. Methods: A critical analysis of nerve injury and regeneration literature concentrating on outcome measures from both immediate and chronically denervated experimental works was conducted. Results: Results of numerous works employing both growth factor and stem cell enhanced nerve guidance conduits have shown encouraging results. However, further research is needed to optimize guidance conduit dynamics, bioavailability and delivery of both growth factors and stem cells to enhance peripheral nerve regeneration and functional recovery. Discussion: This review discusses current animal and clinical growth factor and stem cell studies, specifically focusing on future bio-engineering approaches in developing a nerve guidance conduit in the future. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats. RESEARCH DESIGN AND METHODS--MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number--to--muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated. RESULTS--VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number--to--muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. CONCLUSIONS--These results suggest that MSC transplantation could have therapeutic effects on DPN through paracrine actions of growth factors secreted by MSCs. Diabetes 57: 3099-3107, 2008 [ABSTRACT FROM AUTHOR]

Background: Schwann cells (SC) which are myelin-forming cells in peripheral nervous system are very useful for the treatment of diseases of peripheral nervous system and central nervous system. However, it is difficult to obtain sufficient large number of SC for clinical use, so alternative cell systems are desired. Results: Using a procedure similar to the one used for propagation of neural stem cells, we could induce rat adipose-derived stem cells (ADSC) into floating neurospheres. In addition to being able to differentiate into neuronal- and glial-like cells, neurospheres could be induced to differentiate into SC-like cells. SC-like cells were bi- or tri-polar in shape and immunopositive for nestin and SC markers p75, GFAP and S-100, identical to genuine SC. We also found that SC-like cells could induce the differentiation of SH-SY5Y neuroblastoma cells efficiently, perhaps through secretion of soluble substances. We showed further that SC-like cells could form myelin structures with PC12 cell neurites in vitro. Conclusion: These findings indicated that ADSC could differentiate into SC-like cells in terms of morphology, phenotype and functional capacities. SC-like cells induced from ADSC may be useful for the treatment of neurological diseases. [ABSTRACT FROM AUTHOR]

The sensory nerve is highly involved in lower extremity wound healing. In diabetic and vascular diseases, impaired nerve function and blood flow delay wound healing. Tissue regeneration using adult stem cells is a targeted therapeutic modality in disorders of nerve and blood supply. Effective delivery using an autologous vascularized fascial flap as a vehicle of stem cells leads to severed sensory nerve recovery, local tissue blood flow, and wound healing. Human MSCs (hMSCs) were transfected with green fluorescent protein (GFP) cDNA and tested for efficiency and proliferation in vitro. The nude rat model with femoral vessel and saphenous nerve severance and ligation was wrapped with a vascularized epigastric flap for GFP-hMSC, fibroblast growth factor-2 (FGF-2), or a combination of both after 2 weeks. Maximum nerve conduction velocity recovered to 70% of the presurgical level in the GFP-hMSC- and FGF-2-treated group at 2 weeks. Blood flow and nerve conduction velocity were positively correlated at 1 week. Wound healing in the ipsilateral paw had significantly improved by 1 week. Histologically, blood vessels and nerves are very organized, and regenerated neuron immunoreactivity of GAP-43 and a nerve regrowth marker of S-100 were remarkable in the human GFP (hGFP)-hMSC and FGF-2-treated group at 2 weeks; therefore, sensory nerve regeneration, blood flow, and wound healing were improved by the administration of stem cells and FGF-2 via a vascularized flap. This may be implicated in clinical denervated and reduced circulation tissue wound healing. [ABSTRACT FROM AUTHOR]

Ionising radiation-induced normal tissue damage is a major concern in clinic and public health. It is the most limiting factor in radiotherapy treatment of malignant diseases. It can also cause a serious harm to populations exposed to accidental radiation exposure or nuclear warfare. With regard to the clinical use of radiation, there has been a number of modalities used in the field of radiotherapy. These includes physical modalities such modified collimators or fractionation schedules in radiotherapy. In addition, there are a number of pharmacological agents such as essential fatty acids, vasoactive drugs, enzyme inhibitors, antioxidants, and growth factors for the prevention or treatment of radiation lesions in general. However, at present, there is no standard procedure for the treatment of radiation-induced normal tissue lesions. Stem cells and their role in tissue regeneration have been known to biologists, in particular to radiobiologists, for many years. It was only recently that the potential of stem cells was studied in the treatment of radiation lesions. Stem cells, immediately after their successful isolation from a variety of animal and human tissues, demonstrated their likely application in the treatment of various diseases. This paper describes the types and origin of stem cells, their characteristics, current research, and reviews their potential in the treatment and regeneration of radiation induced normal tissue lesions. Adult stem cells, among those mesenchymal stem cells (MSCs), are the most extensively studied of stem cells. This review focuses on the effects of MSCs in the treatment of radiation lesions. [ABSTRACT FROM AUTHOR]

(1) Background: Emerging interest of physicians to use adipose-derived stem cells (ADSCs) for regenerative therapies and the fact that low-dose irradiation (LD-IR ≤ 0.1 Gy) has been reported to enhance the proliferation of several human normal and bone-marrow stem cells, but not that of tumor cells, lead to the idea of improving stem cell therapies via low-dose radiation. Therefore, the aim of this study was to investigate unwanted side effects, as well as proliferation-stimulating mechanisms of LD-IR on ADSCs. (2) Methods: To avoid donor specific effects, ADSCs isolated from mamma reductions of 10 donors were pooled and used for the radiobiological analysis. The clonogenic survival assay was used to classify the long-term effects of low-dose radiation in ADSCs. Afterwards, cytotoxicity and genotoxicity, as well as the effect of irradiation on proliferation of ADSCs were investigated. (3) Results: LD (≤ 0.1 Gy) of ionizing radiation promoted the proliferation and survival of ADSCs. Within this dose range neither geno- nor cytotoxic effects were detectable. In contrast, greater doses within the dose range of >0.1–2.0 Gy induced residual double-strand breaks and reduced the long-term survival, as well as the proliferation rate of ADSCs. (4) Conclusions: Our data suggest that ADSCs are resistant to LD-IR. Furthermore, LD-IR could be a possible mediator to improve approaches of stem cells in the field of regenerative medicine. [ABSTRACT FROM AUTHOR]