A new 'spin' on neural stem cells?

The existence of neural stem cells in the adult brain was essentially denied until the last decade. Within the past ten years, considerable progress has been made in examining the fundamental properties of neural stem cells. Most recently there has been much interest in the identification and precise location of the adult neural stem cells in vivo. Studies examining the localization of neural stem cells are controversial and suggest two distinct locations within the adult brain: the ependymal layer lining the ventricles, and the subependymal layer immediately adjacent to the ependyma.     

Mesenchymal stem cells: weapons or dangers for cancer treatment?

Mesenchymal stem cells (MSC) have attracted recent attention for their cell therapy potential, based in particular on their immunosuppressive properties, which have served as the basis for the treatment of autoimmune diseases. Interestingly, MSC have been used in cell therapy strategies to deliver therapeutical genes. Cell therapy approaches taking advantages of MSC have been proposed, as MSC display a potential tropsim for tumors. However, all these strategies raise a series of questions about the safety of MSC, as MSC could enhance tumor growth and metastasis. This review summarizes recent findngs about MSC in carcinogenesis.     

Antibodies targeting cancer stem cells: A new paradigm in immunotherapy?

Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumor development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumors and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse.Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective.This review will outline the recent discoveries for CSCs across the major tumor types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies and the outlook for the future development of this emerging area will be given.Key words: antibody, targeting, cancer, stem cell, therapyMonoclonal antibodies are clinically and commercially-established therapeutics.^1,2 A great deal of progress has been made over the last 30 years in overcoming problems and translating the phenomenal amount of laboratory research into clinical products. However, antibodies or other molecular interventions against cancer do not necessarily cure. In many cases, they can increase survival and improve quality of life. So, have we been hitting the wrong targets? Certainly, receptors such as human epidermal growth factor-1 (HER1/EGFR), HER2, CD20 and growth factors such as vascular endothelial cell (VEGF) and Interleukin-6 (IL-6) are involved in the cancer process, but have we been overlooking the real culprits?This review aims to examine the biology of cancer stem cells considering the markers defining them and their survival and will describe the new antibody-focused strategies emerging to target them for more effective treatment of cancer.     

Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases.     

Metastatic cancer stem cells: A new target for anti-cancer therapy?

Over the past few years, supporting evidence for the cancer stem cell hypothesis has been provided for an increasing number of tumor entities. According to this hypothesis, only a small population of undifferentiated cells with stem cell characteristics has the ability to form tumors through asymmetric division and subsequent differentiation of the progeny into the heterogeneous cell types that comprise a tumor. Recently, we were able to show that cancer stem cells are not only responsible for tumorigenesis, but that they contain a subpopulation characterized by CXCR4 expression which is exclusively capable of disseminating and subsequently providing the substrate for tumor metastasis. Of note, these recent advances in our understanding of cancer stem cell biology raise more questions than they answer. Some of these arising questions regarding the targeted elimination of these cancer stem cells will be addressed in this perspective.     

Antibodies targeting cancer stem cells: A new paradigm in immunotherapy?

Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumour development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumours and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse.

Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective.

This review will outline the recent discoveries for CSCs across the major tumour types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies will be given and the outlook for the future development of this emerging area will be given.     

Mesenchymal stem cells for multiple sclerosis: does neural differentiation really matter?

The lack of therapies fostering remyelination and regeneration of the neural network deranged by the autoimmune attack occurring in multiple sclerosis (MS), is raising great expectations about stem cells therapies for tissue repair. Mesenchymal stem cells (MSCs) have been proposed as a possible treatment for MS due to the reported capacity of transdifferentiation into neural cells and their ability at modulating immune responses. However, recent studies have demonstrated that many other functional properties are likely to play a role in the therapeutic plasticity of MSCs, including anti-apoptotic, trophic and anti-oxidant effects. These features are mostly based on the paracrine release of soluble molecules, often dictated by local environmental cues. Based on the modest evidence of long-term engraftment and the striking clinical effects that are observed immediately after MSCs administration in the experimental model of MS, we do not favor a major role for transdifferentiation as an important mechanism involved in the therapeutic effect of MSCs.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Mesenchymal stem cells in the treatment of spinal cord injuries:A review

With technological advances in basic research,the intricate mechanism of secondary delayed spinal cord injury(SCI)continues to unravel at a rapid pace.However,despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord,the cure for paralysis remains elusive.Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI.R ecent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results.An array of mesenchymal stem cells(MSCs)from various sources with novel and promising strategies are being developed to improve function after SCI.In this review,we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI.We will discuss the progress of MSCs application in research,focusing on the neuroprotective properties of MSCs.Finally,we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Brain mesenchymal stem cells:The other stem cells of the brain?

Multipotent mesenchymal stromal cells(MSC),have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation.The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair.However,some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist.In brain,perivascular MSCs like pericytes and adventitial cells,could constitute another stem cell population distinct to the neural stem cell pool.The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes,the demonstration of neural biomarkers expression,electrophysiological recordings,and the absence of cell fusion.The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells.It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Mesenchymal stem cells in treating autism:Novel insights

Autism spectrum disorders(ASDs)are complex neurodevelopmental disorders characterized by dysfunctions in social interactions,abnormal to absent verbal communication,restricted interests,and repetitive stereotypic verbal and non-verbal behaviors,influencing the ability to relate to and communicate.The core symptoms of ASDs concern the cognitive,emotional,and neurobehavioural domains.The prevalence of autism appears to be increasing at an alarming rate,yet there is a lack of effective and definitive pharmacological options.This has created an increased sense of urgency,and the need to identify novel therapies.Given the growing awareness of immune dysregulation in a significant portion of the autistic population,cell therapies have been proposed and applied to ASDs.In particular,mesenchymal stem cells(MSCs)possess the immunological properties which make them promising candidates in regenerative medicine.MSC therapy may be applicable to several diseases associated with inflammation and tissue damage,where subsequent regeneration and repair is necessary.MSCs could exert a positive effect in ASDs through the following mechanisms:stimulation of repair in the damaged tissue,e.g.,inflammatory bowel disease;synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors;integrating into existing neural and synaptic network,and restoring plasticity.The paracrine mechanisms of MSCs show interesting potential in ASD treatment.Promising and impressive results have been reported from the few clinical studies published to date,although the exact mechanisms of action of MSCs in ASDs to restore functions are still largely unknown.The potential role of MSCs in mediating ASD recovery is discussed in light of the newest findings from recent clinical studies.     

Mesenchymal stem cells and their use in therapy: What has been achieved?

The considerable therapeutic potential of human multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) has generated increasing interest in a wide variety of biomedical disciplines. Nevertheless, researchers report studies on MSCs using different methods of isolation and expansion, as well as different approaches to characterize them; therefore, it is increasingly difficult to compare and contrast study outcomes. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposed minimal criteria to define human MSCs. First, MSCs must be plastic-adherent when maintained in standard culture conditions (α minimal essential medium plus 20% fetal bovine serum). Second, MSCs must express CD105, CD73 and CD90, and MSCs must lack expression of CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules. Third, MSCs must differentiate into osteoblasts, adipocytes and chondroblasts in vitro. MSCs are isolated from many adult tissues, in particular from bone marrow and adipose tissue. Along with their capacity to differentiate and transdifferentiate into cells of different lineages, these cells have also generated great interest for their ability to display immunomodulatory capacities. Indeed, a major breakthrough was the finding that MSCs are able to induce peripheral tolerance, suggesting that they may be used as therapeutic tools in immune-mediated disorders. Although no significant adverse events have been reported in clinical trials to date, all interventional therapies have some inherent risks. Potential risks for undesirable events, such as tumor development, that might occur while using these stem cells for therapy must be taken into account and contrasted against the potential benefits to patients.     

Adult neural stem cells: an endogenous tool to repair brain injury?

Research on stem cells has developed as one of the most promising areas of neurobiology. In the beginning of the 1990s, neurogenesis in the adult brain was indisputably accepted, eliciting great research efforts. Neural stem cells in the adult mammalian brain are located in the ‘neurogenic’ areas of the subventricular and subgranular zones. Nevertheless, many reports indicate that they subsist in other regions of the adult brain. Adult neural stem cells have arisen considerable interest as these studies can be useful to develop new methods to replace damaged neurons and treat severe neurological diseases such as neurodegeneration, stroke or spinal cord lesions. In particular, a promising field is aimed at stimulating or trigger a self‐repair system in the diseased brain driven by its own stem cell population. Here, we will revise the latest findings on the characterization of active and quiescent adult neural stem cells in the main regions of neurogenesis and the factors necessary to maintain their active and resting states, stimulate migration and homing in diseased areas, hoping to outline the emerging knowledge for the promotion of regeneration in the brain based on endogenous stem cells.     

A polarized anchor for hematopoietic stem cells: Synapse between stem cells and their niche?

Multipotent hematopoietic stem cells are maintained by the bone marrow niche, but how niche-derived membrane-bound stem cell factor (mSCF) regulates HSCs remains unclear. In this issue, Hao et al. (2021. J. Cell Biol. https://doi.org/10.1083/jcb.202010118) describe that mSCF, synergistically with VCAM-1, induces large, polarized protrusions that serve as anchors for HSCs to their niche.

Hematopoietic stem cells (HSCs) generate all blood and immune cells throughout life via self-renewal and multilineage differentiation within the bone marrow niche. HSCs are the basis for bone marrow transplantation, saving thousands of lives yearly. The bone marrow niche often serves as a paradigm for studying stem cell biology. In addition, elucidating the underlying mechanism in the niche helps devise strategies to expand functional HSCs for clinical use. Within the niche, leptin receptor–positive perisinusoidal stromal cells and endothelial cells are the major source of essential cytokines for HSC maintenance, including vascular cell adhesion molecule 1 (VCAM-1) and stem cell factor (SCF; 1, 2). Locally produced soluble and membrane-bound cytokines preserve the unique localization and anchorage of HSCs to stromal cells within their niche. Consistent with this notion, mouse genetic data have shown that membrane-bound SCF (mSCF) is important for HSC maintenance in vivo (3). However, given that both soluble and membrane-bound forms of SCF can engage with the cognate cKIT receptors, the mechanisms by which mSCF sustains HSCs function in vivo remain elusive. Likewise, it is unclear why the expansion and maintenance of HSCs ex vivo by adding SCF to culture as an either soluble or immobilized form has only been achieved with limited success.In this issue, Hao et al. addressed this question by using a supported lipid bilayer (SLB) system to model the interaction between HSCs and membrane-bound cytokines, including SCF (4). SLBs present an advantage over conventional immobilization methods; they allow the lateral mobility of membrane-bound proteins and clustering of receptors and signaling complexes, thus resembling the lipid bilayer of plasma membrane in vivo. Focusing on HSC cytokines that may be presented as membrane-bound forms in the bone marrow niche, the authors performed an imaging screen in vitro using SLBs and found that mSCF but not soluble SCF (sSCF) induced mSCF/cKIT clustering and the formation of membrane protrusions on HSCs. While mSCF alone was sufficient to promote cell protrusions, HSCs required both mSCF and VCAM-1 for large, polarized protrusions. They followed HSCs at different time points after exposure to VCAM-1 and mSCF by scanning electron microscopy and observed that HSCs first formed diffuse mSCF clusters and multifocal thin protrusions and then proceeded to a polarized, clustered morphology with larger and thicker protrusions. Using a controlled sheer stress device, Hao et al. showed that these polarized protrusions had a functional consequence on the adhesion strength of HSCs. mSCF and VCAM-1 dramatically increased the adhesion of HSCs to SLB compared with VCAM-1 or mSCF alone. Interestingly, the effect was more prominent in HSCs compared with their immediate downstream progenies, multipotent progenitors. This phenotype was also specific to ligands presented on SLB because the effect was canceled when the cytokines were directly immobilized onto the glass surface. Then, they had a close look into the cytoskeletal organization of HSCs in the presence of both mSCF and VCAM-1 on SLB. They found that F-actin and myosin IIa concentrated at the protrusion, which led them to speculate that the cytoskeleton remodeling mediates the formation of the polarized morphology. Indeed, chemical inhibitors blocking myosin contraction, actin polymerization, or Rho-associated protein kinase disrupted the formation of the large and polarized protrusion. The authors noted that phosphatidylinositol 3-kinase (PI3K) also localized with mSCF/cKIT clusters, so they further assessed the contribution of the PI3K/Akt pathway to the polarized morphology of HSCs by using total internal reflection fluorescence microscopy and PI3K and Akt chemical inhibitors. PI3K/Akt activation contributed downstream of the mSCF–VCAM-1 synergy to regulating HSC cell adhesion and polarized mSCF/cKIT distribution. In addition, PI3K signaling enhanced the nuclear retention of FOXO3a, a crucial factor for HSC self-renewal; this enhancement was induced by mSCF but lessened by sSCF. Intriguingly, sSCF also competed with mSCF and abrogated the effect of the mSCF–VCAM-1 synergy on polarized protrusion formation. However, whether and how PI3K transmits the mSCF–VCAM-1 synergy into proliferation or quiescence cues in HSCs requires further investigation. Taken together, these data suggest that mSCF and VCAM-1 synergize to induce polarized protrusions on HSCs, which regulates their adhesion to the niche (Fig. 1). These protrusions share many features with the immunological synapse (5), which points toward the existence of a similar model for stem cells, “stem cell synapse,” where HSCs interact with and receive a variety of signals from their niche cells.Open in a separate windowFigure 1.VCAM-1 and mSCF synergistically promote the formation of polarized protrusions (stem cell synapse) on HSCs. (A and B) VCAM-1 or mSCF alone does not induce apparent polarized morphology on HSCs. The signaling and adhesion of HSCs to the niche is not at its full potential. (C) VCAM-1 and mSCF together induce robust receptor clustering on HSCs, optimal signaling, and strong adhesion. (D) sSCF can competitively disrupt the polarized protrusions on HSCs. The figure was created with BioRender.com.While the study by Hao et al. sheds light on how niche signals, particularly mSCF, regulate HSCs, several outstanding questions remain. First, even though many hematopoietic cells express cKIT (some of them even express higher levels than HSCs), HSCs respond to mSCF + VCAM-1 the strongest by recruiting the most mSCF to clusters. What is the specific mechanism in HSCs underlying this specificity? Second, SCF is produced both as mSCF and sSCF in vivo, through alternative splicing and proteolytic cleavage; if mSCF is mainly responsible for anchoring HSCs in the niche, what is the function of sSCF in vivo? Does sSCF modulate the available pool of mSCF? Third, robust maintenance of HSCs in culture has been challenging. HSCs can be maintained in a system composed of sSCF, thromopoietin (TPO), fibronectin, and polyvinyl alcohol (6). Tethering cytokines to SLB elicits more physiological response from HSCs compared with soluble cytokines or direct immobilization. Does SLB improve maintenance of HSCs in in vitro culture? Fourth, some cytokines, such as TPO, act on HSCs in a long-range manner (7). How do these systemic cytokines induce robust signaling in HSCs? Do they participate in the stem cell synapse even if they are not the initiators? Finally, do stem cells and their niche interact by forming similar synapses in other stem cell systems? Answering these questions will deepen our understanding of the stem cell niche and help integrate the niche component into potential, more successful applications in regenerative medicine.     

Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair?

Mesenchymal Stem Cells (MSCs) are a bone marrow-derived population present in adult tissues that possess the important property of dividing when called upon and of differentiating into specialized cells. The evidence that MSCs were able to transdifferentiate into specialized cells of tissues different from bone marrow, in particular into nervous cells, opened up the possibility of using MSCs to substitute damaged neurons, that are normally not replaced but lost, in order to repair the Nervous System. The first neuronal differentiation protocols were based on the use of a mixture of toxic drugs which induced MSCs to rapidly acquire a neuronal-like morphology with the expression of specific neuronal markers. However, many subsequent studies demonstrated that the morphological and molecular modifications of MSCs were probably due to a stress response, rather than to a real differentiation into neuronal cells, thus throwing into question the possible use of MSCs to repair the nervous system. Currently, some papers are suggesting again that it may be possible to induce neuronal differentiation of MSCs by using several differentiation protocols, and by accompanying the morphological evidence of differentiation with functional evidence, thus demonstrating that MSC-derived cells not only seem to be neurons, but that they also function like neurons. In this review, we have attempted to shed light on the capacity of MSCs to genuinely differentiate into nervous cells, and to identify the most reliable protocols for obtaining neurons from MSCs for nervous system repair.     

Mesenchymal stem cells in acute lung injury: are they ready for translational medicine?

Acute lung injury (ALI) is a severe clinical condition responsible for high mortality and the development of multiple organ dysfunctions, because of the lack of specific and effective therapies for ALI. Increasing evidence from pre‐clinical studies supports preventive and therapeutic effects of mesenchymal stem cells (MSCs, also called mesenchymal stromal cells) in ALI/ARDS (acute respiratory distress syndrome). Therapeutic effects of MSCs were noticed in various delivery approaches (systemic, local, or other locations), multiple origins (bone marrow or other tissues), or different schedules of administrations (before or after the challenges). MSCs could reduce the over‐production of inflammatory mediators, leucocyte infiltration, tissue injury and pulmonary failure, and produce a number of benefit factors through interaction with other cells in the process of lung tissue repair. Thus, it is necessary to establish guidelines, standard operating procedures and evaluation criteria for translating MSC‐based therapies into clinical application for patients with ALI.     

Q&A: Mesenchymal stem cells — where do they come from and is it important?

Mesenchymal stem — or stromal — cells (MSCs) have been administered in hundreds of clinical trials for multiple indications, making them some of the most commonly used selected regenerative cells. Paradoxically, MSCs have also long remained the least characterized stem cells regarding native identity and natural function, being isolated retrospectively in long-term culture. Recent years have seen progress in our understanding of the natural history of these cells, and candidate native MSCs have been identified within fetal and adult organs. Beyond basic knowledge, deciphering the biology of innate MSCs may have important positive consequences for the therapeutic use of these cells.     

From human genes to stem cells: new challenges for patent law?

The social controversies that have surrounded human cloning and the use of embryos for research purposes might create unique patent issues for stem cell researchers. Policy makers should learn from the legal and ethical concerns associated with human gene patents and develop coherent patent policies that recognize and clearly address emerging social controversies.     

Multilineage stem cells in the adult: A perivascular legacy?

Mesenchymal stem cells proliferate extensively in cultures of unselected, total cell isolates from multiple fetal and adult organs. Perivascular cells, principally pericytes surrounding capillaries and microvessels, but also adventitial cells located around larger arteries and veins, have been recently identified as possible originators of mesenchymal stem cells, first by phenotypic analogies and eventually following stringent cell sorting. While it is clear that purified perivascular cells exhibit multiple mesodermal developmental potentials and become indistinguishable from conventionally derived mesenchymal stem cells after in vitro culture, the possible roles played by these blood vessel-bound cells in organogenesis and adult tissue repair remain elusive. Unsolved questions regarding the identity of mesenchymal stem cells have not compromised the consideration of these cells as outstanding candidates for cell therapies. Better knowledge of the lineage affiliation, tissue distribution and molecular identity of mesenchymal stem cells will contribute to the development of more efficient, safer therapeutic cells.