Induced pacemaker and Purkinje cells from adult stem cells
Inventors
Alt, Eckhard • KARIMI, Tahereh
Assignees
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Publication Number
US-10905722-B2
Publication Date
2021-02-02
Expiration Date
Abstract
Adult stem cells are reprogrammed to form pacemaker cells and Purkinje cells through the sequential activation of SHOX2>TBX5>HCN2. These Purkinje cells spontaneously surround and connect with the larger pacemaker cells, thus forming an induced sinoatrial body that produces funny current and can make cardiovascular tissues beat in a manner similar to a natural sinoatrial node.
Core Innovation
The disclosed work reprograms adult, autologous, initially unmodified adult stem cells and regenerative cells into non-contractile cardiomyocyte lineages for pacemaker and Purkinje cell fates. The approach induces lineage commitment by sequential epigenetic reprogramming through sequentially expressing SHOX2 before TBX5 before HCN2 (“SHOX2>TBX5>HCN2”), with optional involvement of TBX3/TBX18. Adult tissue-derived stem cells are obtained from a patient and used in the reprogramming to produce pacemaker and Purkinje cardiomyocyte cells.
Following sequential epigenetic reprogramming, the document reports formation and association of two morphologically distinct cell populations: large “spider-like” pacemaker-like cells and small spindle/Purkinje-like cells. These induced populations are described as forming an induced sinoatrial body or induced sinus node-like structure. The induced sinoatrial body is characterized by expression of cardiac conduction/pacemaker markers, including CX30.2 and HCN4, and by producing funny current (If).
The induced cell populations are additionally supported by downstream marker assessment and electrophysiology, including qPCR marker upregulation and patch-clamp evidence of If. The overall system is positioned as producing pacemaker and conduction system phenotypes through the sequential transcription factor program and associating the induced pacemaker-like and Purkinje-like cells within an induced sinoatrial body.
Claims Coverage
The document contains one independent claim, directed to a method of treating an arrhythmia with a specific sequential epigenetic reprogramming sequence and then introducing the resulting pacemaker and/or Purkinje cardiomyocyte cells into the arrhythmic heart.
Sequential epigenetic reprogramming for Purkinje and pacemaker lineage commitment
Inducing lineage commitment of adult tissue-derived stem cells towards Purkinje and pacemaker cardiomyocyte cells through sequential epigenetic reprogramming by sequentially expressing SHOX2 before TBX5 before HCN2 (“SHOX2>TBX5>HCN2”).
Introduction of induced pacemaker and Purkinje cells into an arrhythmic heart
Introducing said Purkinje cells or said pacemaker cells, or both, into said arrhythmic heart as part of the treatment of an arrhythmia.
Obtaining adult tissue-derived stem cells from a patient with an arrhythmic heart
Obtaining adult tissue-derived stem cells from a patient with an arrhythmic heart prior to inducing lineage commitment.
Overall, the claim coverage centers on obtaining adult tissue-derived stem cells from a patient, inducing Purkinje and pacemaker lineage commitment via sequential epigenetic reprogramming with the specified transcription factor order (SHOX2>TBX5>HCN2), and introducing Purkinje cells and/or pacemaker cells into the patient’s arrhythmic heart.
Stated Advantages
Treating an arrhythmia by generating Purkinje and pacemaker cardiomyocyte cells and introducing them into an arrhythmic heart.
Reprogrammed cells produce funny current (If) and express conduction/pacemaker markers (CX30.2 and HCN4) in the induced sinoatrial body.
Documented Applications
Treating arrhythmias by introducing induced pacemaker and Purkinje cells into an arrhythmic heart, including sick sinus syndrome (sinus node dysfunction) and tachycardic arrhythmias.
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