Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

Application of mesenchymal stem cell therapy for premature ovarian insufficiency: Recent advances from mechanisms to therapeutics

The incidence of premature ovarian insufficiency(POI)is increasing worldwide,particularly among younger women,posing a significant challenge to fertility.In addition to menopausal symptoms,POI leads to several complications that profoundly affect female reproductive function and overall health.Unfortunately,current clinical treatment strategies for this condition are limited and often yield unsatisfactory outcomes.These approaches typically involve hormone repla-cement therapy combined with psychological support.Recently,mesenchymal stem cell(MSC)therapies for POI have garnered considerable attention in global research.MSCs can restore ovarian reproductive and endocrine functions through diverse mechanisms,including controlling differentiation,promoting angiogenesis,regulating ovarian fibrosis,inhibiting apoptosis,enhancing autocrine and paracrine effects,suppressing inflammation,modulating the immune system,and genetic regulation.This editorial offers a succinct summary of the application of MSC therapy in the context of POI,providing evidence for groundbreaking medical approaches that have potential to enhance reproductive health and overall well-being for women.

Stem cell therapy and diabetic erectile dysfunction:A critical review

Erectile dysfunction(ED)has been identified as one of the most frequent chronic complications of diabetes mellitus(DM).The prevalence of ED is estimated to be about 67.4%in all DM cases worldwide.The pathophysiological process leading to ED involves endothelial,neurological,hormonal,and psychological factors.In DM,endothelial and neurological factors play a crucial role.Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM.The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery.However,these treatments are limited in terms of just relieving the symptoms,but not resolving the cause of the problem.The use of stem cells for treating ED is currently being studied mostly in experimental animals.The stem cells used are derived from adipose tissue,bone,or human urine.Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue.However,research on stem cell therapy for ED in humans remains to be limited.Nevertheless,significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.

Stem cell therapy for central nerve system injuries: glial cells hold the key

Mammalian adult central nerve system （CNS） injuries are devastating because of the intrinsic difficulties for effective neuronal regeneration. The greatest problem to be overcome for CNS recovery is the poor regeneration of neurons and myelin-forming cells, oligodendrocytes. Endogenous neural progenitors and transplanted exogenous neuronal stem cells can be the source for neuronal regeneration. However, because of the harsh local microenvironment, they usually have very low efficacy for functional neural regeneration which cannot compensate for the loss of neurons and oligodendrocytes. Glial cells （including astrocytes, microglia, oligodendrocytes and NG2 glia） are the majority of cells in CNS that provide support and protection for neurons. Inside the local microenvironment, glial cells largely influence local and transplanted neural stem cells survival and fates. This review critically analyzes current finding of the roles of glial cells in CNS regeneration, and highlights strategies for regulating glial cells＇ behavior to create a permissive microenvironment for neuronal stem cells.

Autologous bone marrow derived stem cell therapy in patients with type 2 diabetes mellitus-defining adequate administration methods

AIM To carry out randomized trial for evaluating effects of autologous bone marrow derived stem cell therapy(ABMSCT) through different routes.METHODS Bone marrow aspirate was taken from the iliac crest of patients. Bone marrow mononuclear cells were separatedand purified using centrifugation. These cells were then infused in a total of 21 patients comprising three groups of 7 patients each. Cells were infused into the superior pancreaticoduodenal artery(Group Ⅰ), splenic artery(Group Ⅱ) and through the peripheral intravenous route(Group Ⅲ). Another group of 7 patients acted as controls and a sham procedure was carried out on them(Group Ⅳ). The cells were labelled with the PET tracer F18-FDG to see their homing and in vivo distribution. Data for clinical outcome was expressed as mean ± SE. All other data was expressed as mean ± SD. Baseline and post treatment data was compared at the end of six months, using paired t-test. Cases and controls data were analyzed using independent t-test. A probability(P) value of < 0.05 was regarded as statistically significant. Measures of clinical outcome were taken as the change or improvement in the following parameters:(1) C-peptide assay;(2) HOMA-IR and HOMA-B;(3) reduction in Insulin dose; subjects who showed reduction of insulin requirement of more than 50% from baseline requirement were regarded as responders; and(4) reduction in HbA 1c. RESULTS All the patients, after being advised for healthy lifestyle changes, were evaluated at periodical intervals and at the end of 6 mo. The changes in body weight, body mass index, waist circumference and percentage of body fat in all groups were not significantly different at the end of this period. The results of intra-group comparison before and after ABMSCT at the end of six months duration was as follows:(1) the area under C-peptide response curve was increased at the end of 6 mo however the difference remained statistically non-significant(P values for fasting C-peptide were 0.973, 0.103, 0.263 and 0.287 respectively and the P values for stimulated C-peptide were 0.989, 0.395, 0.325 and 0.408 respectively for groups Ⅰ?to Ⅳ);(2) the Insulin sensitivity indices of HOMA IR and HOMA B also did not show any significant differences(P values for HOMA IR were 0.368, 0.223, 0.918 and 0.895 respectively and P values for HOMA B were 0.183, 0.664, 0.206 and 0.618 respectively for groups Ⅰto Ⅳ);(3) Group Ⅰshowed a significant reduction in Insulin dose requirement(P < 0.01). Group Ⅱ patients also achieved a significant reduction in Insulin dosages(P = 0.01). The Group Ⅰand Group Ⅱ patients together constituted the targeted group wherein the feeding arteries to pancreas were used for infusing stem cells. Group Ⅲ, which was the intravenous group, showed a non-significant reduction in Insulin dose requirement(P = 0.137). Group Ⅳ patients which comprised the control arm also showed a significant reduction in Insulin dosages at the end of six months(P < 0.05); and(4) there was a non-significant change in the Hb A1 c levels at the end of 6 mo across all groups(P = 0.355, P = 0.351, P = 0.999 and P = 0.408 respectively for groups Ⅰto Ⅳ). CONCLUSION Targeted route showed a significant reduction in Insulin requirement at the end of six months of study period whereas the intravenous group failed to show reduction.

Stem cell therapy for Alzheimer’s disease:An overview of experimental models and reality

Alzheimer's disease(AD)is a neurodegenerative disorder.The pathology of AD is characterized by extracellular amyloid beta(Aβ)plaques,neurofibrillary tangles com-posed of hyperphosphorylated tau,neuronal death,synapse loss,and brain atrophy.Many therapies have been tested to improve or at least effectively modify the course of AD.Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease.Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction,although certain weak-nesses or limitations need to be overcome.This review recapitulates rodent models for AD,the therapeutic efficacy of stem cells,influencing factors,and the underlying mechanisms behind these changes.Stem cell therapy provides perspective and chal-lenges for its clinical application in the future.

Mesenchymal stem cell therapy for retinal ganglion cell neuroprotection and axon regeneration

Retinal ganglion cells （RGCs） are responsible for propagat- ing signals derived from visual stimuli in the eye to the brain, along their axons within the optic nerve to the superior colliculus, lateral geniculate nucleus and visu- al cortex of the brain. Damage to the optic nerve either through trauma, such as head injury, or degenerative dis- ease, such as glaucoma causes irreversible loss of function through degeneration of non-regenerating RGC axons and death of irreplaceable RGCs, ultimately leading to blindness （Berry et al., 2008）. The degeneration of RGCs and their axons is due to the loss of the necessary source of retrogradely transported neurotrophic factors （NTFs） being hindered by axonal injury. NTFs are survival factors for neurons and play a pivotal part in axon regeneration. Stem cells particularly mesenchymal stem cells （MSCs） have been shown to possess a natural intrinsic capacity for paracrine support, releasing multiple signalling mol- ecules including NTFs. By transplanting MSCs into the vitreous, they are positioned adjacent to the injured reti- na to provide paracrine-mediated therapy for the retinal neuronal cells （Johnson et al., 2010a; Mead et al., 2013）. Additionally, MSCs may be pre-differentiated into sup- portive glial-like cells, such as Schwann cells, which could further increase their potential for paracrine support of injured neurons （Martens et al., 2013）. Thus, MSCs have received considerable attention as a new cellular therapy for both traumatic and degenerative eye disease, acting as an alternative source of NTFs, protecting injured RGCs and promoting regeneration of their axons （Figure 1）.

Effect of microenvironment modulation on stem cell therapy for spinal cord injury pain

Spinal cord injury （SCI） currently ranks second after mental retarda- tion among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissues （Yezierski, 2005; D＇Angelo et al., 2013）.

Quantification of corneal neovascularization after ex vivo limbal epithelial stem cell therapy

AIM: To assess cultured limbal epithelial stem cell transplantation in patients with limbal stem cell deficiency by analyzing and quantifying corneal neovascularization.METHODS: This retrospective, interventional case series included eight eyes with total limbal stem cell deficiency. Ex vivo limbal epithelial stem cells were cultured on human amniotic membrane using an animalfree culture method. The clinical parameters of limbal stem cell deficiency, impression cytology, and quantification of corneal neovascularization were evaluated before and after cultured limbal stem cell transplantation. The area of corneal neovascularization,vessel caliber(VC), and invasive area(IA) were analyzed before and after stem cell transplantation by image analysis software. Best-corrected visual acuity(BCVA),epithelial transparency, and impression cytology were also measured.RESULTS: One year after surgery, successful cases showed a reduction(improvement) of all three parameters of corneal neovascularization [neovascular area(NA), VC, IA], while failed cases did not. NA decreased a mean of 32.31%(P =0.035), invasion area29.37%(P =0.018) and VC 14.29%(P =0.072). BCVA improved in all eyes(mean follow-up, 76 ±21mo).Epithelial transparency improved significantly from 2.00 ±0.93 to 0.88±1.25(P =0.014). Impression cytology showed that three cases failed after limbal epithelial stem cell therapy before 1y of follow-up.CONCLUSION: This method of analyzing andmonitoring surface vessels is useful for evaluating the epithelial status during follow-up, as successful cases showed a bigger reduction in corneal neovascularization parameters than failed cases. Using this method,successful cases could be differentiated from failed cases.

Stem cell therapy for insulin-dependent diabetes:Are we still on the road?

In insulin-dependent diabetes,the isletβcells do not produce enough insulin and the patients must receive exogenous insulin to control blood sugar.However,there are still many deficiencies in exogenous insulin supplementation.Therefore,the replacement of destroyed functionalβcells with insulin-secreting cells derived from functional stem cells is a good idea as a new therapeutic idea.This review introduces the development schedule of mouse and human embryonic islets.The differences between mouse and human pancreas embryo development were also listed.Accordingly to the different sources of stem cells,the important research achievements on the differentiation of insulin-secretingβcells of stem cells and the current research status of stem cell therapy for diabetes were reviewed.Stem cell replacement therapy is a promising treatment for diabetes,caused by defective insulin secretion,but there are still many problems to be solved,such as the biosafety and reliability of treatment,the emergence of tumors during treatment,untargeted differentiation and autoimmunity,etc.Therefore,further understanding of stem cell therapy for insulin is needed.

Stem cell therapy: A promising treatment for COVID-19

Novel coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has become a global pandemic.SARSCoV-2 is an RNA virus and has a glycosylated spike(S)protein used for genome encoding.COVID-19 can lead to a cytokine storm and patients usually have early respiratory signs and further secondary infections,which can be fatal.COVID-19 has entered an emergency phase,but there are still no specific effective drugs for this disease.Mesenchymal stem cells(MSCs)are multipotent stromal cells,which cause antiapoptosis and can repair damaged epithelial cells.Many clinical trials have proved that MSC therapy could be a potential feasible therapy for COVID-19 patients,especially those with acute respiratory distress syndrome,without serious adverse events or toxicities.However,more studies are needed in the future,in order to confirm the effect of this therapy.

Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease

Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy(SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate endpoints. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used-especially left ventricle ejection fraction(LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2 D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3 D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.

Pancreatic transplant surgery and stem cell therapy:Finding the balance between therapeutic advances and ethical principles

The latest achievements in the field of pancreas transplantation and stem cell therapy require an effort by the scientific community to clarify the ethical implications of pioneering treatments,often characterized by high complexity from a surgical point of view,due to transplantation of multiple organs at the same time or at different times,and from an immunological point of view for stem cell therapy.The fundamental value in the field of organ transplants is,of course,a solidarity principle,namely that of protecting the health and life of people for whom transplantation is a condition of functional recovery,or even of survival.The nature of this value is that of a concept to which the legal discipline of transplants entrusts its own ethical dignity and for which it has ensured a constitutional recognition in different systems.The general principle of respect for human life,both of the donor and of the recipient,evokes the need not to put oneself and one’s neighbor in dangerous conditions.The present ethical reflection aims to find a balance between the latest therapeutic advances and several concepts including the idea of the person,the respect due to the dead,the voluntary nature of the donation and the consent to the same,the gratuitousness of the donation,the scientific progress and the development of surgical techniques,and the policies of health promotion.

Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes

Type 1 diabetes mellitus(T1DM)is a chronic autoimmune disease caused by the specific destruction of pancreatic isletβcells and is characterized as the absolute insufficiency of insulin secretion.Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications.Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM.However,it is restricted by many factors such as severe shortage of donor sources,progressive loss of donor cells,high cost,etc.As pluripotent stem cells have the potential to give rise to all cells including isletβcells in the body,stem cell therapy for diabetes has attracted great attention in the academic community and the general public.Transplantation of isletβ-like cells differentiated from human pluripotent stem cells(hPSCs)has the potential to be an excellent alternative to islet transplantation.In stem cell therapy,obtainingβcells with complete insulin secretion in vitro is crucial.However,after much research,it has been found that theβ-like cells obtained by in vitro differentiation still have many defects,including lack of adult-type glucose stimulated insulin secretion,and multihormonal secretion,suggesting that in vitro culture does not allows for obtaining fully matureβ-like cells for transplantation.A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human isletβcells.Furthermore,PDX1,NKX6.1,SOX9,NGN3,PAX4,etc.,are important in inducing hPSC differentiation in vitro.The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functionalβ-like cells in vitro.This article reviewsβcell maturation in vivo and in vitro and the vital roles of key molecules in this process,in order to explore the current problems in stem cell therapy for diabetes.

Stem cell therapy for glaucoma-there is still a long way to go

Glaucoma is now the second leading reason of blindness in the world and is characterized by gradual loss of retinal ganglion cells.Stem cells have the ability to regenerate human structures.Although there are still problems unsolved,stem cell therapy might provide brighter future for treatment of glaucoma.

The therapeutic potential of stem cell therapy for myocardial infraction

It has been researched that myocardial infarction(MI)has drastically affected patients all over the world.The current guidelines of the medical treatments including PTCA or CABG just improve the condition and reduce damage to an extent.In the new studies and recent updates on myocardial stem cells,it has been researched that myocardial stem cells have regenerative capacity.Stem cell therapy used in cardiac disease management shows a promising and novel approach for cardiac tissues,cardiac muscle repair,and regeneration.Furthermore,it’s been observed that the stem cell-derived paracrine factors help in regulating and remodeling the coronary artery inflammation and cardiac tissue generation in the MI region.Here,we highlight recent findings and discuss how they use stem cell therapy during MI and heart disease.

Stem cell-based ischemic stroke therapy:Novel modifications and clinical challenges

Ischemic stroke(IS)causes severe disability and high mortality worldwide.Stem cell(SC)therapy exhibits unique therapeutic potential for IS that differs from current treatments.SC’s cell homing,differentiation and paracrine abilities give hope for neuroprotection.Recent studies on SC modification have enhanced therapeutic effects for IS,including gene transfection,nanoparticle modification,biomaterial modification and pretreatment.Thesemethods improve survival rate,homing,neural differentiation,and paracrine abilities in ischemic areas.However,many problems must be resolved before SC therapy can be clinically applied.These issues include production quality and quantity,stability during transportation and storage,as well as usage regulations.Herein,we reviewed the brief pathogenesis of IS,the“multi-mechanism”advantages of SCs for treating IS,various SC modification methods,and SC therapy challenges.We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.

The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.