Conductive Hydrogel Restores Electrical Conduction to Promote Neurological Recovery in a Rat Model.

Spinal cord injury (SCI), caused by significant physical trauma, as well as other pathological conditions, results in electrical signaling disruption and loss of bodily functional control below the injury site. Conductive biomaterials have been considered a promising approach for treating SCI, owing to their ability to restore electrical connections between intact spinal cord portions across the injury site. In this study, we evaluated the ability of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to restore electrical signaling and improve neuronal regeneration in a rat SCI model generated using the compression clip method. Gelatin or PAMB-G was injected at the SCI site, yielding three groups: Control (saline), Gelatin, and PAMB-G. During the 8-week study, PAMB-G, compared to Control, had significantly lower proinflammatory factor expression, such as for tumor necrosis factor -α (0.388 ± 0.276 for PAMB-G vs. 1.027 ± 0.431 for Control) and monocyte chemoattractant protein (MCP)-1 (0.443 ± 0.201 for PAMB-G vs. 1.662 ± 0.912 for Control). In addition, PAMB-G had lower astrocyte and microglia numbers (35.75 ± 4.349 and 40.75 ± 7.890, respectively) compared to Control (50.75 ± 6.5 and 64.75 ± 10.72) and Gelatin (48.75 ± 4.787 and 71.75 ± 7.411). PAMB-G-treated rats also had significantly greater preservation and regeneration of remaining intact neuronal tissue (0.523 ± 0.059% mean white matter in PAMB-G vs 0.377 ± 0.044% in Control and 0.385 ± 0.051% in Gelatin) caused by reduced apoptosis and increased neuronal growth-associated gene expression. All these processes stemmed from PAMB-G facilitating increased electrical signaling conduction, leading to locomotive functional improvements, in the form of increased Basso-Beattie-Bresnahan scores and steeper angles in the slope test (76.667 ± 5.164 for PAMB-G, vs. 59.167 ± 4.916 for Control and 58.333 ± 4.082 for Gelatin), as well as reduced gastrocnemius muscle atrophy (0.345 ± 0.085 for PAMB-G, vs. 0.244 ± 0.021 for Control and 0.210 ± 0.058 for Gelatin). In conclusion, PAMB-G injection post-SCI resulted in improved electrical signaling conduction, which contributed to lowered inflammation and apoptosis, increased neuronal growth, and greater bodily functional control, suggesting its potential as a viable treatment for SCI.

A Novel Conductive Polypyrrole-Chitosan Hydrogel Containing Human Endometrial Mesenchymal Stem Cell-Derived Exosomes Facilitated Sustained Release for Cardiac Repair.

Myocardial infarction (MI) results in cardiomyocyte necrosis and conductive system damage, leading to sudden cardiac death and heart failure. Studies have shown that conductive biomaterials can restore cardiac conduction, but cannot facilitate tissue regeneration. This study aims to add regenerative capabilities to the conductive biomaterial by incorporating human endometrial mesenchymal stem cell (hEMSC)-derived exosomes (hEMSC-Exo) into poly-pyrrole-chitosan (PPY-CHI), to yield an injectable hydrogel that can effectively treat MI. In vitro, PPY-CHI/hEMSC-Exo, compared to untreated controls, PPY-CHI, or hEMSC-Exo alone, alleviates H2O2-induced apoptosis and promotes tubule formation, while in vivo, PPY-CHI/hEMSC-Exo improves post-MI cardiac functioning, along with counteracting against ventricular remodeling and fibrosis. All these activities are facilitated via increased epidermal growth factor (EGF)/phosphoinositide 3-kinase (PI3K)/AKT signaling. Furthermore, the conductive properties of PPY-CHI/hEMSC-Exo are able to resynchronize cardiac electrical transmission to alleviate arrythmia. Overall, PPY-CHI/hEMSC-Exo synergistically combines the cardiac regenerative capabilities of hEMSC-Exo with the conductive properties of PPY-CHI to improve cardiac functioning, via promoting angiogenesis and inhibiting apoptosis, as well as resynchronizing electrical conduction, to ultimately enable more effective MI treatment. Therefore, incorporating exosomes into a conductive hydrogel provides dual benefits in terms of maintaining conductivity, along with facilitating long-term exosome release and sustained application of their beneficial effects.

Uterine Immunoprivileged Cells Restore Cardiac Function of Male Recipients After Myocardial Infarction.

It has been documented that the uterus plays a key cardio-protective role in pre-menopausal women, which is supported by uterine cell therapy, to preserve cardiac functioning post-myocardial infarction, being effective among females. However, whether such therapies would also be beneficial among males is still largely unknown. In this study, we aimed to fill in this gap in knowledge by examining the effects of transplanted uterine cells on infarcted male hearts. We identified, based on major histocompatibility complex class I (MHC-I) expression levels, 3 uterine reparative cell populations: MHC-I(neg), MHC-I(mix), and MHC-I(pos). In vitro, MHC-I(neg) cells showed higher levels of pro-angiogenic, pro-survival, and anti-inflammatory factors, compared to MHC-I(mix) and MHC-I(pos). Furthermore, when cocultured with allogeneic mixed leukocytes, MHC-I(neg) had lower cytotoxicity and leukocyte proliferation. In particular, CD8+ cytotoxic T cells significantly decreased, while CD4+CD25+ Tregs and CD4-CD8- double-negative T cells significantly increased when cocultured with MHC-I(neg), compared to MHC-I(mix) and MHC-I(pos) cocultures. In vivo, MHC-I(neg) as well as MHC-I(mix) were found under both syngeneic and allogeneic transplantation in infarcted male hearts, to significantly improve cardiac function and reduce the scar size, via promoting angiogenesis in the infarcted area. All of these findings thus support the view that males could also benefit from the cardio-protective effects observed among females, via cell therapy approaches involving the transplantation of immuno-privileged uterine reparative cells in infarcted hearts.

Heart Failure Impairs Bone Marrow Hematopoietic Stem Cell Function and Responses to Injury.

Background Heart failure (HF) is a clinical syndrome associated with a progressive decline in myocardial function and low-grade systemic inflammation. Chronic inflammation can have lasting effects on the bone marrow (BM) stem cell pool by impacting cell renewal and lineage differentiation. However, how HF affects BM stem/progenitor cells remains largely unexplored. Methods and Results EGFP+ (Enchanced green fluorescent protein) mice were subjected to coronary artery ligation, and BM was collected 8 weeks after myocardial infarction. Transplantation of EGFP+ BM into wild-type mice revealed reduced reconstitution potential of BM from mice subjected to myocardial infarction versus BM from sham mice. To study the effects HF has on human BM function, 71 patients, HF (n=20) and controls (n=51), who were scheduled for elective cardiac surgery were consented and enrolled in this study. Patients with HF exhibited more circulating blood myeloid cells, and analysis of patient BM revealed significant differences in cell composition and colony formation potential. Human CD34+ cell reconstitution potential was also assessed using the NOD-SCID-IL2rγnull mouse xenotransplant model. NOD-SCID-IL2rγnull mice reconstituted with BM from patients with HF had significantly fewer engrafted human CD34+ cells as well as reduced lymphoid cell production. Analysis of tissue repair responses using permanent left anteriordescending coronary artery ligation demonstrated reduced survival of HF-BM reconstituted mice as well as significant differences in human (donor) and mouse (host) cellular responses after MI. Conclusions HF alters the BM composition, adversely affects cell reconstitution potential, and alters cellular responses to injury. Further studies are needed to determine whether restoring BM function can impact disease progression or improve cellular responses to injury.

A Polypyrrole-Polycarbonate Polyurethane Elastomer Alleviates Cardiac Arrhythmias via Improving Bio-Conductivity.

Myocardial fibrosis, resulting from myocardial infarction (MI), significantly alters cardiac electrophysiological properties. As fibrotic scar tissue forms, its resistance to incoming action potentials increases, leading to cardiac arrhythmia, and eventually sudden cardiac death or heart failure. Biomaterials are gaining increasing attention as an approach for addressing post-MI arrhythmias. The current study investigates the hypothesis that a bio-conductive epicardial patch can electrically synchronize isolated cardiomyocytes in vitro and rescue arrhythmic hearts in vivo. A new conceived biocompatible, conductive, and elastic polyurethane composite bio-membrane, referred to as polypyrrole-polycarbonate polyurethane (PPy-PCNU), is developed, in which solid-state conductive PPy nanoparticles are distributed throughout an electrospun aliphatic PCNU nanofiber patch in a controlled manner. Compared to PCNU alone, the resulting biocompatible patch demonstrates up to six times less impedance, with no conductivity loss over time, as well as being able to influence cellular alignment. Furthermore, PPy-PCNU promotes synchronous contraction of isolated neonatal rat cardiomyocytes and alleviates atrial fibrillation in rat hearts upon epicardial implantation. Taken together, epicardially-implanted PPy-PCNU could potentially serve as a novel alternative approach for the treatment of cardiac arrhythmias.

Optimizing human endometrial mesenchymal stem cells for maximal induction of angiogenesis.

Human endometrial mesenchymal stem cells (hEMSCs) have been shown to promote neo-vascularization; however, its angiogenic function lessens with age. To determine the optimal conditions for maximizing hEMSC angiogenic capacity, we examined the effects of serial passaging on hEMSC activity. hEMSCs were cultured from passages (P) 3, 6, 9, and 12, and analyzed for proliferation, migration, differentiation and senescence, as well as their capacity to induce angiogenesis. The results showed that hEMSC proliferation and migration significantly decreased after P12. Furthermore, hEMSC differentiation into adipogenic and osteogenic lineages, as well as their proangiogenic capacity, gradually decreased from P9-12, while senescence only occurred after P12. Evaluation of angiogenic-related protein levels showed that both transforming growth factor ß2 and Tie-2 was significantly reduced in hEMSCs at P12, compared to P3, possibly serving as the basis behind their lowered angiogenic capacity. Furthermore, in vivo angiogenesis evaluation with Matrigel plug assay showed that the optimal hEMSC to HUVEC ratio, for maximizing vessel formation, was 1:4. This study showed that hEMSC passaging was associated with lowered cellular functioning, bringing them closer to a senescent phenotype, especially after P12, thereby defining the optimal time period for cultivating fully functional hEMSCs for therapeutic applications.

Phenotypic expansion of KCNH1-associated disorders to include isolated epilepsy and its associations with genotypes and molecular sub-regional locations.

PURPOSE: Genotype-phenotypic correlation of KCNH1 variant remains elusive. This study aimed to expand the phenotypic spectrum of KCNH1 and explore the correlations between epilepsy and molecular sub-regional locations. METHODS: We performed whole-exome sequencing in a cohort of 98 patients with familiar febrile seizure (FS) or epilepsy with unexplained etiologies. The damaging effects of variants were predicted by protein modeling and multiple in silico tools. All reported patients with KCNH1 pathogenic variants with detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype correlation. RESULTS: Two novel KCNH1 variants were identified in three cases, including two patients with FS with inherited variant (p.Ile113Thr) and one boy with epilepsy with de novo variant (p.Arg357Trp). Variant Ile113Thr was located within the eag domain, and variant p.Arg357Trp was located in transmembrane domain 4 of KCNH1, respectively. Two patients experienced refractory status epilepticus (SE), of which one patient died of acute encephalopathy induced by SE. Further analysis of 30 variants in 51 patients demonstrated that de novo variants were associated with epileptic encephalopathy, while mosaic/somatic or germline variants cause isolated epilepsy/FS. All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1. CONCLUSIONS: We found two novel missense variants of KCNH1 in three individuals with isolated FS/epilepsy. Variants in the KCNH1 cause a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy. The genotypes and variant locations help explaining the phenotypic variation of patients with KCNH1 variant.

Uterus: A Unique Stem Cell Reservoir Able to Support Cardiac Repair via Crosstalk among Uterus, Heart, and Bone Marrow.

Clinical evidence suggests that the prevalence of cardiac disease is lower in premenopausal women compared to postmenopausal women and men. Although multiple factors contribute to this difference, uterine stem cells may be a major factor, as a high abundance of these cells are present in the uterus. Uterine-derived stem cells have been reported in several studies as being able to contribute to cardiac neovascularization after injury. However, our studies uniquely show the presence of an "utero-cardiac axis", in which uterine stem cells are able to home to cardiac tissue to promote tissue repair. Additionally, we raise the possibility of a triangular relationship among the bone marrow, uterus, and heart. In this review, we discuss the exchange of stem cells across different organs, focusing on the relationship that exists between the heart, uterus, and bone marrow. We present increasing evidence for the existence of an utero-cardiac axis, in which the uterus serves as a reservoir for cardiac reparative stem cells, similar to the bone marrow. These cells, in turn, are able to migrate to the heart in response to injury to promote healing.

Stroke-Induced Neurological Dysfunction in Aged Mice Is Attenuated by Preconditioning with Young Sca-1+ Stem Cells.

AIMS: To date, stroke remains one of the leading causes of death and disability worldwide. Nearly three-quarters of all strokes occur in the elderly (>65 years old), and a vast majority of these individuals develop debilitating cognitive impairments that can later progress into dementia. Currently, there are no therapies capable of reversing the cognitive complications which arise following a stroke. Instead, current treatment options focus on preventing secondary injuries, as opposed to improving functional recovery. METHODS: We reconstituted aged (20-month old) mice with Sca-1+ bone marrow (BM) hematopoietic stem cells isolated from aged or young (2-month old) EGFP+ donor mice. Three months later the chimeric aged mice underwent cerebral ischemia/reperfusion by bilateral common carotid artery occlusion (BCCAO), after which cognitive function was evaluated. Immunohistochemical analysis was performed to evaluate host and recipient cells in the brain following BCCAO. RESULTS: Young Sca-1+ cells migrate to the aged brain and give rise to beneficial microglial-like cells that ameliorate stroke-induced loss of cognitive function on tasks targeting the hippocampus and cerebellum. We also found that young Sca-1+ cell-derived microglial-like cells possess neuroprotective properties as they do not undergo microgliosis upon migrating to the ischemic hippocampus, whereas the cells originating from old Sca-1+ cells proliferate extensively and skew toward a pro-inflammatory phenotype following injury. CONCLUSIONS: This study provides a proof-of-principle demonstrating that young BM Sca-1+ cells play a pivotal role in reversing stroke-induced cognitive impairments and protect the aged brain against secondary injury by attenuating the host cell response to injury.

An electro-spun tri-component polymer biomaterial with optoelectronic properties for neuronal differentiation.

Optoelectronic biomaterials have recently emerged as a potential treatment option for neurodegenerative diseases, such as optic macular degeneration. Though initial works in the field have involved bulk heterojunctions mimicking solar panels with photovoltaics (PVs) and conductive polymers (CPs), recent developments have considered abandoning CPs in such systems. Here, we developed a simple antioxidant, biocompatible, and fibrous membrane heterojunction composed of photoactive polymer poly(3-hexylthiophene) (P3HT), polycaprolactone (PCL) and polypyrrole (PPY), to facilitate neurogenesis of PC-12 cells when photo-stimulated in vitro. The photoactive prototype, referred to as PCL-P3HT/PPY, was fabricated via polymerization of pyrrole on electro-spun PCL-P3HT nanofibers to form a membrane. Four experimental groups, namely PCL alone, PCL/PPY, PCL-P3HT and PCL-P3HT/PPY, were tested. In the absence of the CP, PCL-P3HT demonstrated lower cell survival due to increased intracellular reactive oxygen/nitrogen species production. PCL-P3HT/PPY rescued these cells by virtue of scavenging radicals, where the CP, PPY, acted as an antioxidant. Apart from having lower impedance, the material also enhanced neurogenesis of PC-12 cells when photo-stimulated, compared to the traditional PCL-P3HT. Lastly, the in vitro system with PC-12 was used to demonstrate the practicality of the material for potential use as a cellular patch in optic and nerve regeneration. This work demonstrated the importance of maintaining PV-CP heterojunctions while simultaneously providing an optoelectrical platform for neural and optical tissue engineering. STATEMENT OF SIGNIFICANCE: Regeneration and repair of injured nervous systems have always been a major clinical challenge. Stem cell therapy is a promising approach for nerve regeneration, and opto-electrical stimulation, which converts light into an electrical signal, has been shown to efficiently regulate stem cell behaviors with enhanced neurogenesis. We developed a micro-fibrous membrane, composed of photoactive polymer, P3HT, scaffold material PCL and conductive polymer PPY. Our heterojunction system improved cell survival via PPY quenching PCL-P3HT-generated cell-damaging reactive oxygen species. PPY also conducted electrons produced from light-stimulated P3HT to promote neurogenesis. This photoactive microfiber biomaterial has great potential as a highly biocompatible and efficient platform to wirelessly promote neurogenesis and survival. Our approach thus showed possibilities with respect to optical tissue engineering.

Aging impairs human bone marrow function and cardiac repair following myocardial infarction in a humanized chimeric mouse.

Ventricular remodeling following myocardial infarction (MI) is a major cause of heart failure, a condition prevalent in older individuals. Following MI, immune cells are mobilized to the myocardium from peripheral lymphoid organs and play an active role in orchestrating repair. While the effect of aging on mouse bone marrow (BM) has been studied, less is known about how aging affects human BM cells and their ability to regulate repair processes. In this study, we investigate the effect aging has on human BM cell responses post-MI using a humanized chimeric mouse model. BM samples were collected from middle aged (mean age 56.4 ± 0.97) and old (mean age 72.7 ± 0.59) patients undergoing cardiac surgery, CD34+/- cells were isolated, and NOD-scid-IL2rγnull (NSG) mice were reconstituted. Three months following reconstitution, the animals were examined at baseline or subjected to coronary artery ligation (MI). Younger patient cells exhibited greater repopulation capacity in the BM, blood, and spleen as well as greater lymphoid cell production. Following MI, CD34+ cell age impacted donor and host cellular responses. Mice reconstituted with younger CD34+ cells exhibited greater human CD45+ recruitment to the heart compared to mice reconstituted with old cells. Increased cellular responses were primarily driven by T-cell recruitment, and these changes corresponded with greater human IFNy levels and reduced mouse IL-1ß in the heart. Age-dependent changes in BM function led to significantly lower survival, increased infarct expansion, impaired host cell responses, and reduced function by 4w post-MI. In contrast, younger CD34+ cells helped to limit remodeling and preserve function post-MI.

Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism.

BACKGROUND: The human endometrium in premenopausal women is an active site of physiological angiogenesis, with regenerative cells present, suggesting that the endometrium contains adult angiogenic stem cells. In the context of cardiac repair after ischemic injury, angiogenesis is a crucial process to rescue cardiomyocytes. We therefore investigated whether human endometrium-derived stem cells (hEMSCs) can be used for cardiac repair after ischemic injury and their possible underlying mechanisms. METHODS: Comparisons were made between hEMSCs successfully isolated from 22 premenopausal women and human bone marrow mesenchymal stem cells (hBMSCs) derived from 25 age-matched patients. Cell proliferation, migration, differentiation, and angiogenesis were evaluated through in vitro experiments, while the ability of hEMSCs to restore cardiac function was examined by in vivo cell transplantation into the infarcted nude rat hearts. RESULTS: In vitro data showed that hEMSCs had greater proliferative and migratory capacities, whereas hBMSCs had better adipogenic differentiation ability. Human umbilical cord vein endothelial cells, treated with conditioned medium from hEMSCs, had significantly higher tube formation than that from hBMSCs or control medium, indicating greater angiogenic potentials for hEMSCs. In vivo, hEMSC transplantation preserved cardiac function, decreased infarct size, and improved tissue repair post-injury. Cardiac metabolism, assessed by 18F-FDG uptake, showed that 18F-FDG uptake at the infarction area was significantly higher in both hBMSC and hEMSC groups, compared to the PBS control group, with hEMSCs having the highest uptake, suggesting hEMSC treatment improves cardiomyocyte metabolism and survival after injury. Mechanistic assessment of the angiogenic potential for hEMSCS revealed that angiogenesis-related factors angiopoietin 2, Fms-like tyrosine kinase 1, and FGF9 were significantly upregulated in hEMSC-implanted infarcted hearts, compared to the PBS control group. CONCLUSION: hEMSCs, compared to hBMSCs, have greater capacity to induce angiogenesis, and improved cardiac function after ischemic injury.

Age-related defects in autophagy alter the secretion of paracrine factors from bone marrow mononuclear cells.

Bone marrow mononuclear cell therapy improves cardiac repair after myocardial infarction (MI), in-part through signaling to resident cardiac cells, such as fibroblasts, which regulate scar formation. The efficacy of cell therapy declines with age, as aging of both donor and recipient cells decreases repair responses. Autophagy regulates the microenvironment by both extracellular vesicle (EV)-dependent and independent secretion pathways. We hypothesized that age-related autophagy changes in bone marrow cells (BMCs) alter paracrine signaling, contributing to lower cell therapy efficacy. Here, we demonstrate that young Sca-1+ BMCs exhibited a higher LC3II/LC3I ratio compared to old Sca-1+ BMCs, which was accentuated when BMCs were cultured under hypoxia. To examine the effect on paracrine signaling, old cardiac fibroblasts were cultured with conditioned medium (CM) from young and old Sca-1+ BMCs. Young, but not old CM, enhanced fibroblast proliferation, migration, and differentiation, plus reduced senescence. These beneficial effects were lost when autophagy or EV secretion in BMCs was blocked pharmacologically, or by siRNA knockdown of Atg7. Therefore, both EV-dependent and -independent paracrine signaling from young BMCs is responsible for paracrine stimulation of old cardiac fibroblasts. In vivo, bone marrow chimerism of old mice with young BMCs increased the number of LC3b+ cells in the heart compared to old mice reconstituted with old BMCs. These data suggest that the deterioration of autophagy with aging negatively impacts the paracrine effects of BMCs, and provide mechanistic insight into the age-related decline in cell therapy efficacy that could be targeted to improve the function of old donor cells.

Injectable conductive hydrogel can reduce pacing threshold and enhance efficacy of cardiac pacemaker.

Background: Pacemaker implantation is currently used in patients with symptomatic bradycardia. Since a pacemaker is a lifetime therapeutic device, its energy consumption contributes to battery exhaustion, along with its voltage stimulation resulting in local fibrosis and greater resistance, which are all detrimental to patients. The possible resolution for those clinical issues is an injection of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to reduce the myocardial threshold voltage for pacemaker stimulation. Methods: PAMB-G is synthesized by covalently linking PAMB to gelatin, and its conductivity is measured using two-point resistivity. Rat hearts are injected with gelatin or PAMB-G, and pacing threshold is evaluated using electrocardiogram and cardiac optical mapping. Results: PAMB-G conductivity is 13 times greater than in gelatin. The ex vivo model shows that PAMB-G significantly enhances cardiac tissue stimulation. Injection of PAMB-G into the stimulating electrode location at the myocardium has a 4 times greater reduction of pacing threshold voltage, compared with electrode-only or gelatin-injected tissues. Multi-electrode array mapping reveals that the cardiac conduction velocity of PAMB-G group is significantly faster than the non- or gelatin-injection groups. PAMB-G also reduces pacing threshold voltage in an adenosine-induced atrial-ventricular block rat model. Conclusion: PAMB-G hydrogel reduces cardiac pacing threshold voltage, which is able to enhance pacemaker efficacy.

Evidence for the existence of CD34+ angiogenic stem cells in human first-trimester decidua and their therapeutic for ischaemic heart disease.

Stem cell transplantation is nearly available for clinical application in the treatment of ischaemic heart disease (IHD), where it may be joined traditional methods (intervention and surgery). The angiogenic ability of seed cells is essential for this applicability. The aim of this study was to reveal the presence of CD34+ angiogenic stem cells in human decidua at the first trimester and to use their strong angiogenic capacity in the treatment of IHD. In vitro, human decidual CD34+ (dCD34+ ) cells from the first trimester have strong proliferation and clonality abilities. After ruling out the possibility that they were vascular endothelial cells and mesenchymal stem cells (MSCs), dCD34+ cells were found to be able to form tube structures after differentiation. Their angiogenic capacity was obviously superior to that of bone marrow mesenchymal stem cells (BMSCs). At the same time, these cells had immunogenicity similar to that of BMSCs. Following induction of myocardial infarction (MI) in adult rats, infarct size decreased and cardiac function was significantly enhanced after dCD34+ cell transplantation. The survival rate of cells increased, and more neovasculature was found following dCD34+ cell transplantation. Therefore, this study confirms the existence of CD34+ stem cells with strong angiogenic ability in human decidua from the first trimester, which can provide a new option for cell-based therapies for ischaemic diseases, especially IHD.

Transplanted microvessels improve pluripotent stem cell-derived cardiomyocyte engraftment and cardiac function after infarction in rats.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer an unprecedented opportunity to remuscularize infarcted human hearts. However, studies have shown that most hiPSC-CMs do not survive after transplantation into the ischemic myocardial environment, limiting their regenerative potential and clinical application. We established a method to improve hiPSC-CM survival by cotransplanting ready-made microvessels obtained from adipose tissue. Ready-made microvessels promoted a sixfold increase in hiPSC-CM survival and superior functional recovery when compared to hiPSC-CMs transplanted alone or cotransplanted with a suspension of dissociated endothelial cells in infarcted rat hearts. Microvessels showed unprecedented persistence and integration at both early (~80%, week 1) and late (~60%, week 4) time points, resulting in increased vessel density and graft perfusion, and improved hiPSC-CM maturation. These findings provide an approach to cell-based therapies for myocardial infarction, whereby incorporation of ready-made microvessels can improve functional outcomes in cell replacement therapies.

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction.

The importance of the immune system for cardiac repair following myocardial infarction is undeniable; however, the complex nature of immune cell behavior has limited the ability to develop effective therapeutics. This limitation highlights the need for a better understanding of the function of each immune cell population during the inflammatory and resolution phases of cardiac repair. The development of reliable therapies is further complicated by aging, which is associated with a decline in cell and organ function and the onset of cardiovascular and immunological diseases. Aging of the immune system has important consequences on heart function as both chronic cardiac inflammation and an impaired immune response to cardiac injury are observed in older individuals. Several studies have suggested that rejuvenating the aged immune system may be a valid therapeutic candidate to prevent or treat heart disease. Here, we review the basic patterns of immune cell behavior after myocardial infarction and discuss the autonomous and nonautonomous manners of hematopoietic stem cell and immune cell aging. Lastly, we identify prospective therapies that may rejuvenate the aged immune system to improve heart function such as anti-inflammatory and senolytic therapies, bone marrow transplant, niche remodeling and regulation of immune cell differentiation.

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors.

BACKGROUND: Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy. METHODS: Here we implanted hematopoietic stem cells (HSCs) from young or old (2- or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution. RESULTS: Regardless of donor age, GFP+ cells homed to the brain of old recipients and expressed the macrophage/microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP+/Iba1+ cells from young and old donors were differentially polarized to an anti- and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively. CONCLUSION: Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.