Adult stem cells in neural repair: Current options, limitations and perspectives

Stem cells represent a promising step for the future of regenerative medicine. As they are able to differentiate into any cell type, tissue or organ, these cells are great candidates for treatments against the worst diseasesthat defy doctors and researchers around the world. Stem cells can be divided into three main groups:(1) embryonic stem cells;(2) fetal stem cells; and(3) adult stem cells. In terms of their capacity for proliferation, stem cells are also classified as totipotent, pluripotent or multipotent. Adult stem cells, also known as somatic cells, are found in various regions of the adult organism, such as bone marrow, skin, eyes, viscera and brain. They can differentiate into unipotent cells of the residing tissue, generally for the purpose of repair. These cells represent an excellent choice in regenerative medicine, every patient can be a donor of adult stem cells to provide a more customized and efficient therapy against various diseases, in other words, they allow the opportunity of autologous transplantation. But in order to start clinical trials and achieve great results, we need to understand how these cells interact with the host tissue, how they can manipulate or be manipulated by the microenvironment where they will be transplanted and for how long they can maintain their multipotent state to provide a full regeneration.

Translational research of adult stem cell therapy

Congestive heart failure(CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.

Adult stem cells as a tool for kidney regeneration

Kidney regeneration is a challenging but promising strategy aimed at reducing the progression to end-stage renal disease(ESRD) and improving the quality of life of patients with ESRD. Adult stem cells are multipotent stem cells that reside in various tissues, such as bone marrow and adipose tissue. Although intensive studies to isolate kidney stem/progenitor cells from the adult kidney have been performed, it remains controversial whether stem/progenitor cells actually exist in the mammalian adult kidney. The efficacy of mesenchymal stem cells(MSCs) in the recovery of kidney function has been demonstrated in animal nephropathy models, such as acute tubular injury, glomerulonephritis, renal artery stenosis, and remnant kidney. However, their beneficial effects seem to be mediated largely via their paracrine effects rather than their direct differentiation into renal parenchymal cells. MSCs not only secrete bioactive molecules directly into the circulation, but they also release various molecules, such as proteins, m RNA, and micro RNA, in membrane-covered vesicles. A detailed analysis of these molecules and an exploration of the optimal combination of these molecules will enable the treatment of patients with kidney disease without using stem cells. Another option for the treatment of patients with kidney disease using adult somatic cells is a direct/indirect reprogramming of adult somatic cells into kidney stem/progenitor cells. Although many hurdles still need to be overcome, this strategy will enable bona fide kidney regeneration rather than kidney repair using remnant renal parenchymal cells.

Clinical trials using dental stem cells:2022 update

For nearly 20 years,dental stem cells(DSCs)have been successfully isolated from mature/immature teeth and surrounding tissue,including dental pulp of permanent teeth and exfoliated deciduous teeth,periodontal ligaments,dental follicles,and gingival and apical papilla.They have several properties(such as self-renewal,multidirectional differentiation,and immunomodulation)and exhibit enormous potential for clinical applications.To date,many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis,periapical lesions,periodontitis,cleft lip and palate,acute ischemic stroke,and so on,and DSC-based therapies obtained satisfactory effects in most clinical trials.In these studies,no adverse events were reported,which suggested the safety of DSC-based therapy.In this review,we outline the characteristics of DSCs and summ-arize clinical trials and their safety as DSC-based therapies.Meanwhile,we also present the current limitations and perspectives of DSC-based therapy(such as harvesting DSCs from inflamed tissue,applying DSC-conditioned medi-um/DSC-derived extracellular vesicles,and expanding-free strategies)to provide a theoretical basis for their clinical applications.

Biological character of human adipose-derived adult stem cells and influence of donor age on cell replication in culture

To investigate the biological character of human adipose-derived adult stem cells (hADAS cells) when cultured in vitro and the relationship between hADAS cell’s replication activity and the donor’s age factor, and to assess the stem cells as a new source for tissue engineering. hADAS cells are isolated from human adipose tissue of different age groups (from adolescents to olds: <20 years old, 21―40 years old, 41―60 years old and >61 years old groups). The protein markers (CD29, CD34, CD44, CD45, CD49d, HLA-DR, CD106) of hADAS cells were detected by flow cytometry (FCM) to identify the stem cell, and the cell cycle was examined for P20 hADAS cells to evaluate the safety of the subculture in vitro. The generative activity of hADAS cells in different age groups was also examined by MTT method. The formula “ log2T D = t logN t ? logN 0” was used to get the time doubling (TD) of the cells. The results showed that the cells kept heredity stabilization by chromosome analysis for at least 20 passages. The TD of these cells increased progressively by ageing, and the TD of the <20 years old group was lower than that of the >61 years old group (statistical analysis of variance (ANOVA), P=0.002, P<0.05). These find- ings suggested that a higher level of hADAS cells replication activity was found in the younger dona- tors, and they represent novel and valuable seed cells for studies of tissue engineering.

Human adult stem cells from menstrual blood and endometrial tissue

The article "Plasticity of human menstrual blood stem cells derived from the endometrium" by Lin et al. (2011), published in Journal of Zhejiang University- SCIENCE B (Biomedicine & Biotechnology),

Adult human neural stem cell therapeutics: Current developmental status and prospect

Over the past two decades, regenerative therapies using stem cell technologies have been developed for various neurological diseases. Although stem cell therapy is an attractive option to reverse neural tissue damage and to recover neurological deficits, it is still under development so as not to show significant treatment effects in clinical settings. In this review, we discuss the scientific and clinical basics of adult neural stem cells(a NSCs), and their current developmental status as cell therapeutics for neurological disease. Compared with other types of stem cells, a NSCs have clinical advantages, such as limited proliferation, inborn differentiation potential into functional neural cells, and no ethical issues. In spite of the merits of a NSCs, difficulties in the isolation from the normal brain, and in the in vitro expansion, have blocked preclinical and clinical study using a NSCs. However, several groups have recently developed novel techniques to isolate and expand a NSCs from normal adult brains, and showed successful applications of a NSCs to neurological diseases. With new technologies for a NSCs and their clinical strengths, previous hurdles in stem cell therapies for neurological diseases could be overcome, to realize clinically efficacious regenerative stem cell therapeutics.

On the“plasticity”of adult stem cells and its application in regenerative medicine

In recent years, with the increasingly further studies on embryonic stem cells and the recognition of the biologic characteristics of adult stem cells, it has been discovered that adult stem cells have another phenomenon of "Plasticity" in addition to the characteristics of strong poten- tial for self-renewal, proliferation and multi-differentiation, which brings us the hope for regenerative medicine —— renewing new organ or tissue cells to replace those damaged by injury or diseases. Although the mechanism of "Plastic- ity" and its application in the regenerative medicine are still in doubt, thorough exploration in these subjects would open up broad prospects for the use in cell and tissue engineering in the near future.

Adult neural stem cells in the mammalian central nervous system

神经干细胞(NSC ) 不仅在胚胎的发展期间而且在所有哺乳动物的种类的成年大脑是在场的，包括人。在 vivo 的干细胞壁龛建筑学使成年 NSC 能连续地在整个生活在特定的大脑区域产生功能的神经原。成年神经发生过程服从于动态规定由各种各样生理，病理学并且药理学刺激。Multipotent 成年 NSC 也看起来内在地塑料，对基因编程顺从在正常区别期间，并且到 epigenetic reprograming 在进 pluripotency 的 de 区别期间。增加的证据建议成年 NSC 显著地在生理、病理学的条件下面贡献专业化神经功能。充分理解成年 NSC 的生物学将提供关键卓见进病原学和主要大脑混乱的潜在的治疗学的干预。这里，我们在哺乳动物的中央神经系统的成年 NSC 上考察最近的进步，包括他们在癌症和再生药的身份，壁龛，功能，粘性，和新兴的角色上的话题。

Application of Chinese Herbal Medicines to Revitalize Adult Stem Cells for Tissue Regeneration

它被建立了在最近成年干细胞玩的几十年在织物更新和新生的一个关键角色。干细胞在某些机关找到的成年人能区分进象巨噬细胞和骨头房间那样的功能的实体。造血的干细胞(HSC ) 和间充质的干细胞(MSC ) 是成年干细胞的二张最重要的人口。这些干细胞的应用程序在对待各种各样的病理学的条件提供新卓见，通过填满由转弯在上或离开区分的特定的函数的房间在静止干细胞壁龛以内编程序。除了那，他们也是有能力的通过发行量旅行，移居到损害地点并且区分提高新生过程。最近，中国药(厘米) 出现了是潜在的候选人为织物新生激活成年干细胞。这评论总结我们的自己，以及其它有关在规定的中草药的使用的调查结果在组织修理和返老还童成年干细胞区别和他们的运动处理。很多中国植物被用作治疗学新陈代谢的混乱上的代理人和大概预防的代理人。按照我们的意见成年干细胞自我新生的激活不仅提供一个新奇方法修理织物损坏，而且减少不利地改变人的正常新陈代谢使遭到的指向的药的使用。

Banking of perinatal mesenchymal stem/stromal cells for stem cellbased personalized medicine over lifetime:Matters arising

Mesenchymal stromal/stem cells(MSCs)are currently applied in regenerative medicine and tissue engineering.Numerous clinical studies have indicated that MSCs from different tissue sources can provide therapeutic benefits for patients.MSCs derived from either human adult or perinatal tissues have their own unique advantages in their medical practices.Usually,clinical studies are conducted by using of cultured MSCs after thawing or short-term cryopreserved-then-thawed MSCs prior to administration for the treatment of a wide range of diseases and medical disorders.Currently,cryogenically banking perinatal MSCs for potential personalized medicine for later use in lifetime has raised growing interest in China as well as in many other countries.Meanwhile,this has led to questions regarding the availability,stability,consistency,multipotency,and therapeutic efficiency of the potential perinatal MSC-derived therapeutic products after longterm cryostorage.This opinion review does not minimize any therapeutic benefit of perinatal MSCs in many diseases after short-term cryopreservation.This article mainly describes what is known about banking perinatal MSCs in China and,importantly,it is to recognize the limitation and uncertainty of the perinatal MSCs stored in cryobanks for stem cell medical treatments in whole life.This article also provides several recommendations for banking of perinatal MSCs for potentially future personalized medicine,albeit it is impossible to anticipate whether the donor will benefit from banked MSCs during her/his lifetime.

Comparison of phenotypic markers and neural differentiation potential of multipotent adult progenitor cells and mesenchymal stem cells

AIM: To compare the phenotypic and neural differentiation potential of human bone marrow derived multipotent adult progenitor cells (MAPC) and mesenchymal stem cells (MSC). METHODS: Cultures of MAPC and MSC were established in parallel from same samples of human bone marrow (n = 5). Both stem cell types were evaluated for expression of pluripotency markers including Oct-4 and Nanog by immunocytochemistry and reversetranscription polymerase chain reaction (RT-PCR) and expression of standard mesenchymal markers including CD14, CD34, CD44, CD45, CD73, CD90, CD105 andhuman leukocyte antigen (HLA)-ABC by flow cytometry. After treatment with neural induction medium both MAPC and MSC were evaluated for expression of neural proteins [neuronal filament-200 (NF-200) and glial fibrillar acidic protein (GFAP)] by immunocytochemistry and Western blotting and neural genes [NF-200, GFAP, Tau, microtubule-associated protein (MAP)-1B, MAP-2, neuron-specific enolase (NSE) and oligodendrocyte-1 (Olig-1)] by quantitative real-time-PCR. RESULTS: MAPC had small trigonal shaped while MSC had elongated spindle-shaped morphology. The MAPC expressed Oct-4 and Nanog both at gene and protein levels, whereas MSC were negative for these pluripotent markers. MAPC were negative for HLA-ABC while MSC had high expression of HLA-ABC. In addition, MAPC as compared to MSC had significantly lower expression of CD44 (36.56% ± 1.92% vs 98.23% ± 0.51%), CD73 (15.11% ± 2.24% vs 98.53% ± 2.22%) and CD105 (13.81% ± 3.82%vs 95.12% ± 5.65%) (P < 0.001, for all) MAPC cultures compared to MSC cultures treated with neural induction medium had significantly higher fold change expression of NF-200 (0.64), GFAP (0.52), Tau (0.59), MAP-2 (0.72), Olig-1 (0.18) and NSE (0.29) proteins (P < 0.01 for Olig-1 and P < 0.001 for rest) as well as higher fold change expression of genes of NF-200 (1.34),GFAP (1.12),Tau (1.08),MAP-1B (0.92), MAP-2 (1.14) andNSE (0.4) (P < 0.001 for all). CONCLUSION: MAPC can be differentially characterized from MSC as Oct-4 and Nanog positive stem cells with no expression of HLA-ABC and low expression of mesenchymal markers CD44, CD73 and CD105 and when compared to MSC they possess greater predilection for differentiation into neuro-ectodermal lineage.

Adult neural stem cell dysfunction in the subventricular zone of the lateral ventricle leads to diabetic olfactory defects

Sensitive smell discrimination is based on structural plasticity of the olfactory bulb,which depends on migration and integration of newborn neurons from the subventricular zone.In this study,we examined the relationship between neural stem cell status in the subventricular zone and olfactory function in rats with diabetes mellitus.Streptozotocin was injected through the femoral vein to induce type 1 diabetes mellitus in Sprague-Dawley rats.Two months after injection,olfactory sensitivity was decreased in diabetic rats.Meanwhile,the number of Brd U-positive and Brd U+/DCX+double-labeled cells was lower in the subventricular zone of diabetic rats compared with agematched normal rats.Western blot results revealed downregulated expression of insulin receptorβ,phosphorylated glycogen synthase kinase 3β,and β-catenin in the subventricular zone of diabetic rats.Altogether,these results indicate that diabetes mellitus causes insulin deficiency,which negatively regulates glycogen synthase kinase 3β and enhances β-catenin degradation,with these changes inhibiting neural stem cell proliferation.Further,these signaling pathways affect proliferation and differentiation of neural stem cells in the subventricular zone.Dysfunction of subventricular zone neural stem cells causes a decline in olfactory bulb structural plasticity and impairs olfactory sensitivity in diabetic rats.

Transcriptional regulation of adult neural stem/progenitor cells: tales from the subventricular zone

In rodents,well characterized neurogenic niches of the adult brain,such as the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus,support the maintenance of neural/stem progenitor cells(NSPCs)and the production of new neurons throughout the lifespan.The adult neurogenic process is dependent on the intrinsic gene expression signatures of NSPCs that make them competent for self-renewal and neuronal differentiation.At the same time,it is receptive to regulation by various extracellular signals that allow the modulation of neuronal production and integration into brain circuitries by various physiological stimuli.A drawback of this plasticity is the sensitivity of adult neurogenesis to alterations of the niche environment that can occur due to aging,injury or disease.At the core of the molecular mechanisms regulating neurogenesis,several transcription factors have been identified that maintain NSPC identity and mediate NSPC response to extrinsic cues.Here,we focus on REST,Egr1 and Dbx2 and their roles in adult neurogenesis,especially in the subventricular zone.We review recent work from our and other laboratories implicating these transcription factors in the control of NSPC proliferation and differentiation and in the response of NSPCs to extrinsic influences from the niche.We also discuss how their altered regulation may affect the neurogenic process in the aged and in the diseased brain.Finally,we highlight key open questions that need to be addressed to foster our understanding of the transcriptional mechanisms controlling adult neurogenesis.

Allogenic banking of dental pulp stem cells for innovative therapeutics

Medical research in regenerative medicine and cellbased therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells(DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products(ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen(HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues(dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice(GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.

Role of stem cell therapies in treating chronic wounds:A systematic review

BACKGROUND The impairment of cutaneous wound healing results in chronic,non-healing wounds that are caused by altered wound environment oxygenation,tissue injury,and permissive microbial growth.Current modalities for the treatment of these wounds inadequately address the complex changes involved in chronic wound pathogenesis.Consequently,stem cell therapies have emerged as a potential therapeutic modality to promote cutaneous regeneration through trophic and paracrine activity.AIM To investigate current literature regarding use of stem cell therapies for the clinical treatment of chronic,non-healing wounds.METHODS PubMed,EMBASE,Cochrane Library,Web of Science,and Scopus were queried with combinations of the search terms“mesenchymal stem cells,”“adult stem cells,”“embryonic stem cells,”“erythroid precursor cells,”“stem cell therapies,”and“chronic wounds”in order to find relevant articles published between the years of 2000 and 2019 to review a 20-year experience.Reference lists from the articles were reviewed to identify additional pertinent articles.Retrieved manuscripts(reviews,case reports/series,retrospective/prospective studies,and clinical trials)were evaluated by the authors for their depiction of clinical stem cell therapy use.Data were extracted from the articles using a standardized collection tool.RESULTS A total of 43 articles describing the use of stem cell therapies for the treatment of chronic wounds were included in this review.While stem cell therapies have been explored in in vitro and in vivo applications in the past,recent efforts are geared towards assessing their clinical role.A review of the literature revealed that adipose-derived stem cells,bone marrow-derived stem cells,bone marrowderived mononuclear cells,epidermally-derived mesenchymal stem cells,fibroblast stem cells,keratinocyte stem cells,placental mesenchymal stem cells,and umbilical cord mesenchymal stem cells have all been employed in the treatment of chronic wounds of various etiologies.Most recently,embryonic stem cells have emerged as a novel stem cell therapy with the capacity for multifaceted germ cell layer differentiation.With the capacity for self-renewal and differentiation,stem cells can enrich existing cell populations in chronic wounds in order to overcome barriers impeding the progression of wound healing.Further,stem cell therapies can be utilized to augment cell engraftment,signaling and activity,and resultant patient outcomes.CONCLUSION Assessing observed clinical outcomes,potential for stem cell use,and relevant therapeutic challenges allows wound care stakeholders to make informed decisions regarding optimal treatment approaches for their patients’chronic wounds.

The promise of stem cell-based therapeutics in ophthalmology

The promising role of cellular therapies in the preservation and restoration of visual function has prompted intensive efforts to characterize embryonic, adult, and induced pluripotent stem cells for regenerative purposes. Three main approaches to the use of stem cells have been described: sustained drug delivery, immunomodulation, and differentiation into various ocular structures. Studies of the differentiation capacity of all three types of stem cells into epithelial, neural, glial and vascular phenotypes have reached proof-of-concept in culture, but the correction of vision is still in the early developmental stages, and the requirements for effective in vivo implementation are still unclear. We present an overview of some of the preclinical findings on stem-cell rescue and regeneration of the cornea and retina in acute injury and degenerative disorders.

Stem cell-based approaches: Possible route to hearing restoration?

Disabling hearing loss is the most common sensorineural disability worldwide.It affects around 466 million people and its incidence is expected to rise to around 900 million people by 2050,according to World Health Organization estimates.Most cases of hearing impairment are due to the degeneration of hair cells(HCs)in the cochlea,mechano-receptors that transduce incoming sound information into electrical signals that are sent to the brain.Damage to these cells is mainly caused by exposure to aminoglycoside antibiotics and to some anti-cancer drugs such as cisplatin,loud sounds,age,infections and genetic mutations.Hearing deficits may also result from damage to the spiral ganglion neurons that innervate cochlear HCs.Differently from what is observed in avian and nonmammalian species,there is no regeneration of missing sensory cell types in the adult mammalian cochlea,what makes hearing loss an irreversible process.This review summarizes the research that has been conducted with the aim of developing cell-based strategies that lead to sensory cell replacement in the adult cochlea and,ultimately,to hearing restoration.Two main lines of research are discussed,one directed toward the transplantation of exogenous replacement cells into the damaged tissue,and another that aims at reactivating the regenerative potential of putative progenitor cells in the adult inner ear.Results from some of the studies that have been conducted are presented and the advantages and drawbacks of the various approaches discussed.