Wiley: STEM CELLS: Table of Contents

Bidirectional relationship between cardiac extracellular matrix and cardiac cells in ischemic heart disease

Sun, 05 Dec 2021 20:06:03 -0800

Our review focuses on the cardiac extracellular matrix (ECM) and cardiac fibroblasts (CFs), cardiac-derived progenitor cells (CPCs), and mesenchymal stem cells (MSCs), and their constant interplay in response to tissue development, aging, disease progression, and repair.

Abstract

Ischemic heart diseases (IHDs), including myocardial infarction and cardiomyopathies, are a leading cause of mortality and morbidity worldwide. Cardiac-derived stem and progenitor cells have shown promise as a therapeutic for IHD but are limited by poor cell survival, limited retention, and rapid washout. One mechanism to address this is to encapsulate the cells in a matrix or three-dimensional construct, so as to provide structural support and better mimic the cells' physiological microenvironment during administration. More specifically, the extracellular matrix (ECM), the native cellular support network, has been a strong candidate for this purpose. Moreover, there is a strong consensus that the ECM and its residing cells, including cardiac stem cells, have a constant interplay in response to tissue development, aging, disease progression, and repair. When externally stimulated, the cells and ECM work together to mutually maintain the local homeostasis by initially altering the ECM composition and stiffness, which in turn alters the cellular response and behavior. Given this constant interplay, understanding the mechanism of bidirectional cell-ECM interaction is essential to develop better cell implantation matrices to enhance cell engraftment and cardiac tissue repair. This review summarizes current understanding in the field, elucidating the signaling mechanisms between cardiac ECM and residing cells in response to IHD onset. Furthermore, this review highlights recent advances in native ECM-mimicking cardiac matrices as a platform for modulating cardiac cell behavior and inducing cardiac repair.

The cyclin‐like protein SPY1 overrides reprogramming induced senescence through EZH2 mediated H3K27me3

Sun, 05 Dec 2021 20:06:03 -0800

Reprogramming of normal fibroblasts to induced pluripotent stem cells is characterized by low efficiency due to the upregulation of tumor suppressors and reprogramming-induced senescence (RIS). Spy1 can be combined with classical pluripotency factors to override RIS through activation of EZH2 followed by an increase in trimethylation of histone H3 at the lysine 27 residue.

Abstract

Fully differentiated cells can be reprogrammed through ectopic expression of key transcription factors to create induced pluripotent stem cells. These cells share many characteristics of normal embryonic stem cells and have great promise in disease modeling and regenerative medicine. The process of remodeling has its limitations, including a very low efficiency due to the upregulation of many antiproliferative genes, including cyclin dependent kinase inhibitors CDKN1A and CDKN2A, which serve to protect the cell by inducing apoptotic and senescent programs. Our data reveals a unique cell cycle mechanism enabling mouse fibroblasts to repress cyclin dependent kinase inhibitors through the activation of the epigenetic regulator EZH2 by a cyclin-like protein SPY1. This data reveals that the SPY1 protein is required for reprogramming to a pluripotent state and is capable of increasing reprogramming efficiency.

Cell cycle‐coupled changes in the level of reactive oxygen species support the proliferation of human pluripotent stem cells

Sun, 05 Dec 2021 20:06:03 -0800

The progression of the cell cycle in human pluripotent stem cells is coupled with the oscillation of the reactive oxygen species (ROS) level. The decrease in this level results in the disturbance of the regulation and progression of S-phase, which, in turn, cause the accumulation of DNA breaks and subsequent apoptosis.

Abstract

The study of proliferation regulation in human pluripotent stem cells is crucial to gain insights into understanding the physiology of these cells. However, redox regulation of the pluripotent cell cycle remains largely unexplored. Here, using human embryonic stem cells (hESCs) as well as human induced pluripotent stem cells (hiPSCs), we demonstrate that the level of reactive oxygen species (ROS) in pluripotent cells oscillates in accordance with the cell cycle progression with the peak occurring at transition from S to G₂/M phase of the cycle. A decrease of this level by antioxidants leads to hindered S-phase initiation and progression but does not affect the early-G₁-phase or mitosis. Cells exposed to antioxidants in the early-G₁-phase accumulate the phosphorylated retinoblastoma protein and overcome the restriction point but are unable to accumulate the main regulators of the S phase—CYCLIN A and GEMININ. Based on the previous findings that CYCLIN A stability is affected by redox homeostasis disturbances in somatic cells, we compared the responses to antioxidant treatments in hESCs and in their differentiated fibroblast-like progeny cells (difESCs). In difESCs, similar to hESCs, a decrease in ROS level results in the disruption of S-phase initiation accompanied by a deficiency of the CYCLIN A level. Moreover, in antioxidant-treated cells, we revealed the accumulation of DNA breaks, which was accompanied by activation of the apoptosis program in pluripotent cells. Thus, we conclude that maintaining the physiological ROS level is essential for promotion of proliferation and accurate DNA synthesis in pluripotent cells and their differentiated descendants.

Three‐dimensional migration of human amniotic fluid stem cells involves mesenchymal and amoeboid modes and is regulated by mTORC1

Margit Rosner, Markus Hengstschläger — Sun, 05 Dec 2021 20:06:03 -0800

This study on human amniotic fluid stem cells (hAFSCs) provides the first demonstration that human stem cells exhibit mTORC1-dependent invasive capacity and can concurrently make use of mesenchymal and amoeboid 3D cell migration modes. These results represent an important step toward the full biological characterization of fetal human stem cells with relevance to developmental research and stem cell-based therapy.

Abstract

Three-dimensional (3D) cell migration is an integral part of many physiologic processes. Although being well studied in the context of adult tissue homeostasis and cancer development, remarkably little is known about the invasive behavior of human stem cells. Using two different kinds of invasion assays, this study aimed at investigating and characterizing the 3D migratory capacity of human amniotic fluid stem cells (hAFSCs), a well-established fetal stem cell type. Eight hAFSC lines were found to harbor pronounced potential to penetrate basement membrane (BM)-like matrices. Morphological examination and inhibitor approaches revealed that 3D migration of hAFSCs involves both the matrix metalloprotease-dependent mesenchymal, elongated mode and the Rho-associated protein kinase-dependent amoeboid, round mode. Moreover, hAFSCs could be shown to harbor transendothelial migration capacity and to exhibit a motility-associated marker expression pattern. Finally, the potential to cross extracellular matrix was found to be induced by mTORC1-activating growth factors and reduced by blocking mTORC1 activity. Taken together, this report provides the first demonstration that human stem cells exhibit mTORC1-dependent invasive capacity and can concurrently make use of mesenchymal and amoeboid 3D cell migration modes, which represents an important step toward the full biological characterization of fetal human stem cells with relevance to both developmental research and stem cell-based therapy.

Aryl hydrocarbon receptor controls skin homeostasis, regeneration, and hair follicle cycling by adjusting epidermal stem cell function

Sun, 05 Dec 2021 20:06:03 -0800

Aryl hydrocarbon receptor (AhR) is required for skin homeostasis and hair growth. AhR depletion in keratinocytes and dermal fibroblasts compromises skin regeneration likely because of reduced epidermal stem cells (EpdSCs) numbers. Reconstitution assays suggest a cell autonomous role for AhR in the epidermis. Signaling networks controlling skin homeostasis are AhR regulated in EpdSCs. AhR modulation by physiological ligands may represent a strategy to treat skin pathology.

Abstract

Skin integrity requires constant maintenance of a quiescent, yet responsive, population of stem cells. While interfollicular epidermal progenitors control normal homeostasis, hair follicle stem cells residing within the bulge provide regenerative potential during hair cycle and in response to wounding. The aryl hydrocarbon receptor (AhR) modulates cell plasticity and differentiation and its overactivation results in severe skin lesions in humans. However, its physiological role in skin homeostasis and hair growth is unknown. Reconstitution assays grafting primary keratinocytes and dermal fibroblasts into nude mice and 3-D epidermal equivalents revealed a positive role for AhR in skin regeneration, epidermal differentiation, and stem cell maintenance. Furthermore, lack of receptor expression in AhR−/− mice delayed morphogenesis and impaired hair regrowth with a phenotype closely correlating with a reduction in suprabasal bulge stem cells (α6^lowCD34⁺). Moreover, RNA-microarray and RT-qPCR analyses of fluorescence-activated cell sorting (FACS)-isolated bulge stem cells revealed that AhR depletion impaired transcriptional signatures typical of both epidermal progenitors and bulge stem cells but upregulated differentiation markers likely compromising their undifferentiated phenotype. Altogether, our findings support that AhR controls skin regeneration and homeostasis by ensuring epidermal stem cell identity and highlights this receptor as potential target for the treatment of cutaneous pathologies.

ELF3 mediates IL‐1α induced differentiation of mesenchymal stem cells to inflammatory iCAFs

Linda L. Tran, Truong Dang, Rintu Thomas, David R. Rowley — Sun, 05 Dec 2021 20:06:03 -0800

Mesenchymal stem cells are a progenitor of myofibroblasts and inflammatory carcinoma-associated fibroblasts. The present study identifies ELF3 as an essential transcription factor in the differentiation of this key pro-inflammatory stromal cell type.

Abstract

Stromal cells in the tumor microenvironment regulate the immune landscape and tumor progression. Yet, the ontogeny and heterogeneity of reactive stromal cells within tumors is not well understood. Carcinoma-associated fibroblasts exhibiting an inflammatory phenotype (iCAFs) have been identified within multiple cancers; however, mechanisms that lead to their recruitment and differentiation also remain undefined. Targeting these mechanisms therapeutically may be important in managing cancer progression. Here, we identify the ELF3 transcription factor as the canonical mediator of IL-1α-induced differentiation of prostate mesenchymal stem cells to an iCAF phenotype, typical of the tumor microenvironment. Furthermore, IL-1α-induced iCAFs were subsequently refractive to TGF-β1 induced trans-differentiation to a myofibroblast phenotype (myCAF), another key carcinoma-associated fibroblast subtype typical of reactive stroma in cancer. Restricted trans-differentiation was associated with phosphorylation of the YAP protein, indicating that interplay between ELF3 action and activation of the Hippo pathway are critical for restricting trans-differentiation of iCAFs. Together, these data show that the IL-1α/ELF3/YAP pathways are coordinate for regulating inflammatory carcinoma-associated fibroblast differentiation.

Dopamine regulates adult neurogenesis in the ventricular‐subventricular zone via dopamine D3 angiotensin type 2 receptor interactions

Sun, 05 Dec 2021 20:06:03 -0800

Model of the effects of dopamine in the proliferation of ventricular-subventricular zone cells. Dopamine, via D2-like receptors, upregulates angiotensin AT2 receptor expression, which mediates D2-induced cell proliferation. Dopamine, through D1-like receptors, decreases angiotensin AT1 receptor expression, and AT1 receptors inhibit cell proliferation. See Figure 5 for additional details.

Abstract

Adult neurogenesis is a dynamic and highly regulated process, and different studies suggest that dopamine modulates ventricular-subventricular zone (V-SVZ) neurogenesis. However, the specific role of dopamine and the mechanisms/factors underlying its effects on physiological and pathological conditions such as Parkinson's disease (PD) are not fully understood. Recent studies have described counter-regulatory interactions between renin-angiotensin system (RAS) and dopamine in peripheral tissues and in the nigrostriatal system. We have previously demonstrated that angiotensin receptors regulate proliferation and generation of neuroblasts in the rodent V-SVZ. However, possible interactions between dopamine receptors and RAS in the V-SVZ and their role in alterations of neurogenesis in animal models of PD have not been investigated. In V-SVZ cultures, activation of dopamine receptors induced changes in the expression of angiotensin receptors. Moreover, dopamine, via D2-like receptors and particularly D3 receptors, increased generation of neurospheres derived from the V-SVZ and this effect was mediated by angiotensin type-2 (AT2) receptors. In rats, we observed a marked reduction in proliferation and generation of neuroblasts in the V-SVZ of dopamine-depleted animals, and inhibition of AT1 receptors or activation of AT2 receptors restored proliferation and generation of neuroblasts to control levels. Moreover, intrastriatal mesencephalic grafts partially restored proliferation and generation of neuroblasts observed in the V-SVZ of dopamine-depleted rats. Our data revealed that dopamine and angiotensin receptor interactions play a major role in the regulation of V-SVZ and suggest potential beneficial effects of RAS modulators on the regulation of adult V-SVZ neurogenesis.

Spatiotemporal extracellular matrix modeling for in situ cell niche studies

Sun, 05 Dec 2021 20:06:03 -0800

Spatiotemporal extracellular matrix modeling facilitates the identification of cell-niches by combining decellularized whole organ sections and recellularization with a new algorithm for automatic generation of density maps and cluster-analysis for identification of regions of interest.

Abstract

Extracellular matrix (ECM) components govern a range of cell functions, such as migration, proliferation, maintenance of stemness, and differentiation. Cell niches that harbor stem-/progenitor cells, with matching ECM, have been shown in a range of organs, although their presence in the heart is still under debate. Determining niches depends on a range of in vitro and in vivo models and techniques, where animal models are powerful tools for studying cell-ECM dynamics; however, they are costly and time-consuming to use. In vitro models based on recombinant ECM proteins lack the complexity of the in vivo ECM. To address these issues, we present the spatiotemporal extracellular matrix model for studies of cell-ECM dynamics, such as cell niches. This model combines gentle decellularization and sectioning of cardiac tissue, allowing retention of a complex ECM, with recellularization and subsequent image processing using image stitching, segmentation, automatic binning, and generation of cluster maps. We have thereby developed an in situ representation of the cardiac ECM that is useful for assessment of repopulation dynamics and to study the effect of local ECM composition on phenotype preservation of reseeded mesenchymal progenitor cells. This model provides a platform for studies of organ-specific cell-ECM dynamics and identification of potential cell niches.

Increased lipogenesis is critical for self‐renewal and growth of breast cancer stem cells: Impact of omega‐3 fatty acids

Sun, 05 Dec 2021 20:06:03 -0800

Breast cancer stem cells (BCSC) have a distinct fatty acid profile due to the aberrant expressions of lipogenic enzymes (eg, FAS, SCD1, and FADS1/2), which are highly involved in sustaining their self-renewal, and proliferative capabilities. Omega-3 polyunsaturated fatty acids can effectively suppress the self-renewal and growth of BCSC by downregulation of the lipogenic enzymes, especially SCD1.

Abstract

Aberrant lipid metabolism has recently been recognized as a new hallmark of malignancy, but the characteristics of fatty acid metabolism in breast cancer stem cells (BCSC) and potential interventions targeting this pathway remain to be addressed. Here, by using the in vitro BCSC models, mammosphere-derived MCF-7 cells and HMLE-Twist-ER cells, we found that the cells with stem cell-like properties exhibited a very distinct profile of fatty acid metabolism compared with that of their parental cancer cells, characterized by increased lipogenesis, especially the activity of stearoyl-CoA desaturase 1 (SCD1) responsible for the production of monounsaturated fatty acids, and augmented synthesis and utilization of the omega-6 arachidonic acid (AA). Suppression of SCD1 activity by either enzyme inhibitors or small interfering RNA (siRNA) knockdown strikingly limited self-renewal and growth of the BCSC, suggesting a key role for SCD1 in BCSC proliferation. Furthermore, elevated levels of SCD1 and other lipogenic enzymes were observed in human breast cancer tissues relative to the noncancer tissues from the same patients and correlated with the pathological grades. Interestingly, treatment of BCSC with omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, effectively downregulated the expression of the lipogenic enzymes and markedly suppressed BCSC self-renewal and growth. Dietary supplementation of nude mice bearing BCSC-derived tumors with omega-3 fatty acids also significantly reduced their tumor load. These findings have demonstrated that increased lipogenesis is critical for self-renewal and growth of BCSC, and that omega-3 fatty acids are effective in targeting this pathway to exert their anticancer effect.

Human induced pluripotent stem cell‐derived macrophages ameliorate liver fibrosis

Sun, 05 Dec 2021 20:06:03 -0800

Human induced pluripotent stem cells (iPSCs) are efficiently differentiated into both M1 and M2 macrophages. These cells were used to treat liver fibrosis in an immunodeficient mouse model. This treatment led to improvement in the fibrosis as measured by several complementary assays.

Abstract

With an increasing number of patients with degenerative hepatic diseases, such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metalloproteinases (MMPs) provide an attractive cellular therapy approach. Human induced pluripotent stem cells (iPSCs) are capable of efficiently generating a large-scale, homogenous population of human macrophages using fully defined feeder- and serum-free differentiation protocol. Human iPSC-macrophages exhibit classical surface cell markers and phagocytic activity similar to peripheral blood-derived macrophages. Moreover, gene and cytokine expression analysis reveal that these macrophages can be efficiently polarized to pro-inflammatory M1 or anti-inflammatory M2 phenotypes in presence of LPS + IFN-γ and IL-4 + IL-13, respectively. M1 macrophages express high level of CD80, TNF-α, and IL-6 while M2 macrophages show elevated expression of CD206, CCL17, and CCL22. Here, we demonstrate that treatment of liver fibrosis with both human iPSC-derived macrophage populations and especially M2 subtype significantly reduces fibrogenic gene expression and disease associated histological markers including Sirius Red, αSMA and desmin in immunodeficient Rag2^−/−γc^−/− mice model, making this approach a promising cell-based avenue to ameliorate fibrosis.

Fare Thee Well — STEM CELLS

Ann Murphy — Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page 1563-1564, December 2021.

Author Index

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page E8-E12, December 2021.

Acknowledgment of Reviewers

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page E7-E7, December 2021.

Issue Information

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page i-vii, December 2021.

Cover Image

Sun, 05 Dec 2021 20:06:03 -0800

Skin biopsies harvested 7 days after depilation and stained with H&E reveal higher numbers of anagenic hair follicles in the AhR+/+ than in the AhR−/− mice, suggesting that AhR positively regulates the telogen-to-anagen phase transition and hair growth.

See Rico-Leo et al. beginning on page 1733.

Previews

Stuart P. Atkinson — Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page 1565-1568, December 2021.

Corrigendum

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page E4-E4, December 2021.

Erratum

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page E6-E6, December 2021.

Corrigendum

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page E5-E5, December 2021.

Corrigendum

Sun, 05 Dec 2021 20:06:03 -0800

STEM CELLS, Volume 39, Issue 12, Page E3-E3, December 2021.

Emerging roles of bromodomain protein 4 in regulation of stem cell identity

Anusree Dey, Sheetal Uppal, Jayeeta Giri, Hari Sharan Misra — Sun, 05 Dec 2021 20:06:03 -0800

Bromodomain protein 4 (BRD4) mediated transcription elongation in complex gene regulatory network during different stages of stem cell transitions. BRD4 modulates gene expression by recruiting PTEF-b for successful RNA polymerase II pause release and transcriptional elongation. Treatment with BET inhibitors blocks the transcriptional elongation and expression of pluripotency genes.

Abstract

Understanding the mechanism of fate decision and lineage commitment is the key step for developing novel stem cell applications in therapeutics. This process is coordinately regulated through systematic epigenetic reprogramming and concomitant changes in the transcriptional landscape of the stem cells. One of the bromo- and extra-terminal domain (BET) family member proteins, bromodomain protein 4 (BRD4), performs the role of epigenetic reader and modulates gene expression by recruiting other transcription factors and directly regulating RNA polymerase II elongation. Controlled gene regulation is the critical step in maintenance of stem cell potency and dysregulation may lead to tumor formation. As a key transcriptional factor and epigenetic regulator, BRD4 contributes to stem cell maintenance in several ways. Being a druggable target, BRD4 is an attractive candidate for exploiting its potential in stem cell therapeutics. Therefore, it is crucial to elucidate how BRD4, through its interplay with pluripotency transcriptional regulators, control lineage commitment in stem cells. Here, we systemically review the role of BRD4 in complex gene regulatory network during three specific states of stem cell transitions: cell differentiation, cell reprogramming and transdifferentiation. A thorough understanding of BRD4 mediated epigenetic regulation in the maintenance of stem cell potency will be helpful to strategically control stem cell fates in regenerative medicine.

Epigenetic regulation of neural stem cells: The emerging role of nucleoporins

Claudia Colussi, Claudio Grassi — Sun, 05 Dec 2021 20:06:03 -0800

Cartoon illustrating the contribution of Nups to epigenetic mechanisms in stem cells. (1) Transcription. (2) Heterochromatin formation. (3) Silencing. (4) Topological associated domain formation. (5) miRNA biogenesis and transport. (6) Protein SUMOylation.

Abstract

Nucleoporins (Nups) are components of the nuclear pore complex that, besides regulating nucleus-cytoplasmic transport, emerged as a hub for chromatin interaction and gene expression modulation. Specifically, Nups act in a dynamic manner both at specific gene level and in the topological organization of chromatin domains. As such, they play a fundamental role during development and determination of stemness/differentiation balance in stem cells. An increasing number of reports indicate the implication of Nups in many central nervous system functions with great impact on neurogenesis, neurophysiology, and neurological disorders. Nevertheless, the role of Nup-mediated epigenetic regulation in embryonic and adult neural stem cells (NSCs) is a field largely unexplored and the comprehension of their mechanisms of action is only beginning to be unveiled. After a brief overview of epigenetic mechanisms, we will present and discuss the emerging role of Nups as new effectors of neuroepigenetics and as dynamic platform for chromatin function with specific reference to the biology of NSCs.

A protein‐centric view of in vitro biological model systems for schizophrenia

Sun, 05 Dec 2021 20:06:03 -0800

Schematic diagram of stem-cell derived two-dimensional schizophrenia (SCZ) culture models (left column) vs three-dimensional (3D) SCZ brain organoid models (middle column) to engineer neural networks for translational medicine. SCZ patient cells are reprogrammed toward human induced pluripotent stem cells (hiPSC). Derived 3D brain organoids from hiPSCs serve as a model for further investigations. The application of proteomics and posttranslational modification specific proteomics (PTMomics) on 3D organoids could contribute to a wealth of information regarding the underlying mechanisms of the diseases and cell responses to in vivo settings (right column).

Abstract

Schizophrenia (SCZ) is a severe brain disorder, characterized by psychotic, negative, and cognitive symptoms, affecting 1% of the population worldwide. The precise etiology of SCZ is still unknown; however, SCZ has a high heritability and is associated with genetic, environmental, and social risk factors. Even though the genetic contribution is indisputable, the discrepancies between transcriptomics and proteomics in brain tissues are consistently challenging the field to decipher the disease pathology. Here we provide an overview of the state of the art of neuronal two-dimensional and three-dimensional model systems that can be combined with proteomics analyses to decipher specific brain pathology and detection of alternative entry points for drug development.

Intranasal delivery of mesenchymal stem cells‐derived extracellular vesicles for the treatment of neurological diseases

Shay Herman, Idan Fishel, Daniel Offen — Sun, 05 Dec 2021 20:06:03 -0800

Schematic diagram illustrating the major brain regions affected in neurodegenerative diseases, to which EVs actively migrate following IN administration. The figure presents the key mechanisms and cargo used by MSC-derived EVs to mitigate these pathologies and induce regeneration.

Abstract

Neurological disorders are diseases of the central nervous system (CNS), characterized by a progressive degeneration of cells and deficiencies in neural functions. Mesenchymal stem cells (MSCs) are a promising therapy for diseases and disorders of the CNS. Increasing evidence suggests that their beneficial abilities can be attributed to their paracrine secretion of extracellular vesicles (EVs). Administration of EVs that contain a mixture of proteins, lipids, and nucleic acids, resembling the secretome of MSCs, has been shown to mimic most of the effects of the parental cells. Moreover, the small size and safety profile of EVs provide a number of advantages over cell transplantation. Intranasal (IN) administration of EVs has been established as an effective and reliable way to bypass the blood-brain barrier and deliver drugs to the CNS. In addition to pharmacological drugs, EVs can be loaded with a diverse range of cargo designed to modulate gene expression and protein functions in recipient cells, and lead to immunomodulation, neurogenesis, neuroprotection, and degradation of protein aggregates. In this review, we will explore the proposed physiological pathways by which EVs migrate through the nasal route to the CNS where they can actively target a region of injury or inflammation and exert their therapeutic effects. We will summarize the functional outcomes observed in animal models of neurological diseases following IN treatment with MSC-derived EVs. We will also examine key mechanisms that have been suggested to mediate the beneficial effects of EV-based therapy.

Organoid technology: Current standing and future perspectives

Sun, 05 Dec 2021 20:06:03 -0800

Organoid generation and therapeutic potential.

Abstract

Organoids are powerful systems to facilitate the study of individuals' disorders and personalized treatments. This emerging technology has improved the chance of translatability of drugs for preclinical therapies and mimicking of the complexity of organs, proposing numerous approaches for human disease modeling, tissue engineering, drug development, diagnosis, and regenerative medicine. In this review, we outline the history of organoid technology and summarize its faithful applications, and then we discuss the challenges and limitations encountered by three-dimensional organoids. Finally, we propose that human organoids offer a basic mechanistic infrastructure for “human modeling” systems to prescribe personalized medicines.

State‐of‐play for cellular therapies in cardiac repair and regeneration

Ramana Vaka, Darryl R. Davis — Sun, 05 Dec 2021 20:06:03 -0800

Abstract

Cardiovascular disease is the primary cause of death around the world. For almost two decades, cell therapy has been proposed as a solution for heart disease. In this article, we report on the “state-of-play” of cellular therapies for cardiac repair and regeneration. We outline the progression of new ideas from the preclinical literature to ongoing clinical trials. Recent data supporting the mechanics and mechanisms of myogenic and paracrine therapies are evaluated in the context of long-term cardiac engraftment. This discussion informs on promising new approaches to indicate future avenues for the field.