RESUMEN
Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.
Asunto(s)
Células Madre Pluripotentes Inducidas , Macaca mulatta , Miocitos Cardíacos , Animales , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Diferenciación Celular , Humanos , Trasplante Autólogo , Tomografía de Emisión de Positrones , Factores de Tiempo , Infarto del Miocardio/terapia , Infarto del Miocardio/patologíaRESUMEN
Cardiovascular disease (CVD), especially ischemic heart disease and stroke, is the major cause of death worldwide, accounting for more than one-third of all deaths annually. Hypertension is the most prevalent and modifiable risk factor of CVD-related deaths. The same is true for obesity, which is currently being recognized as a major global epidemic. The prevalence of obesity in the United States has increased dramatically, from 13.4% in 1960 to 36.5% in 2014, with as much as 70.7% of the American adult population being overweight or obese (CDC). Epidemiological studies have shown that obesity predisposes to hypertension and CVD - with the relationship between markers of obesity and blood pressure being almost linear across different populations. In this review, we discuss systemic and pulmonary hypertension in the context of obesity.
Asunto(s)
Enfermedades Cardiovasculares , Hipertensión Pulmonar , Hipertensión , Adulto , Enfermedades Cardiovasculares/epidemiología , Humanos , Hipertensión/epidemiología , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/etiología , Obesidad/epidemiología , Sobrepeso/epidemiología , Prevalencia , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
Autosomal dominant Hyper IgE syndrome (AD-HIES), a rare immune deficiency affecting fewer than one per million people, is caused by heterozygous deleterious mutations in STAT3. STAT3 signaling plays crucial roles in basic cellular functions affecting broad aspects of cellular homeostasis. Accordingly, in addition to immunological deficits, patients experience severe multisystem non-immunological features. Human induced pluripotent stem cells (hiPSC) are well established as in vivo disease models for various human pathologies. We describe the generation of iPSC from three AD-HIES patients. These iPSCs express pluripotency markers, differentiate into three germ layers, have normal karyotype and similar genome identity to parental cells.
Asunto(s)
Diferenciación Celular , Fibroblastos/patología , Células Madre Pluripotentes Inducidas/patología , Síndrome de Job/genética , Síndrome de Job/patología , Mutación , Factor de Transcripción STAT3/genética , Células Cultivadas , Fibroblastos/metabolismo , Genes Dominantes , Humanos , Células Madre Pluripotentes Inducidas/metabolismoRESUMEN
Chemokine receptor 5 (CCR5) is the primary coreceptor for HIV entry into macrophages. Individuals with a homozygous deletion of 32â¯bp in the CCR5 gene (CCR5Δ32) are highly resistant to HIV infection (Samson et al., 1996). Allogeneic stem cell transplantation from a healthy donor with the homozygous CCR5Δ32 variant to an HIV positive individual has demonstrated efficient long-term control of HIV. We identified three individuals with this homozygous CCR5Δ32 variant, and successfully generated induced pluripotent stem cell (iPSC) lines from their dermal fibroblasts. The iPSCs lines carrying homozygous CCR5Δ32 variant displayed phenotypically normal and the potential to differentiation toward the three germ layers.
Asunto(s)
Secuencia de Bases , Homocigoto , Células Madre Pluripotentes Inducidas/metabolismo , Receptores CCR5 , Eliminación de Secuencia , Adulto , Línea Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores CCR5/genética , Receptores CCR5/metabolismoRESUMEN
Nonhuman primate (NHP) models are more predictive than rodent models for developing induced pluripotent stem cell (iPSC)-based cell therapy, but robust and reproducible NHP iPSC-cardiomyocyte differentiation protocols are lacking for cardiomyopathies research. We developed a method to differentiate integration-free rhesus macaque iPSCs (RhiPSCs) into cardiomyocytes with >85% purity in 10 days, using fully chemically defined conditions. To enable visualization of intracellular calcium flux in beating cardiomyocytes, we used CRISPR/Cas9 to stably knock-in genetically encoded calcium indicators at the rhesus AAVS1 safe harbor locus. Rhesus cardiomyocytes derived by our stepwise differentiation method express signature cardiac markers and show normal electrochemical coupling. They are responsive to cardiorelevant drugs and can be successfully engrafted in a mouse myocardial infarction model. Our approach provides a powerful tool for generation of NHP iPSC-derived cardiomyocytes amenable to utilization in basic research and preclinical studies, including in vivo tissue regeneration models and drug screening.
