Kenneth R. Chien's group
The work of the Chien lab has lead to the identification of a high resolution atlas of the progenitor cells that build the human heart, as well as the factors that control their fate, using multiple model systems and core technology platforms. Based on these advances in understanding human cardiogenesis, we are developing new strategies for regenerative therapeutics, and then translating these advances into the biotechnology sector for the benefit of patients with cardiovascular disease.
The central scientific interest of the Chien lab is to understand heart development at the molecular and cellular level, with the ultimate goal of applying the developmental principles, logic, pathways, technology, and model systems to unravel human heart disease.
The human heart, composed of highly diverse cell types, must be assembled into discrete anatomic and functional structures at the earliest stages of fetal life. While the anatomy and physiology of the human cardiovascular system has been extensively studied, the normal development of human heart and dysregulation in disease are poorly understood at the molecular and cellular level.
Our research group plans to provide new insight into several areas of human cardiogenesis, ranging from molecular decoding of human heart development to developing completely novel technologies to control gene expression in the intact heart in vivo.
Such work is highly interdisciplinary, breaking new ground at the intersection of stem cell biology, developmental biology, biotechnology of modified RNA therapeutics, in vivo delivery, large animal model systems, and cardiovascular biology and medicine.
Keywords: Stem cells, Developmental Biology, Heart Disease, Heart Development, Genetics, Biotechnology
Decoding Human Cardiogenesis
Using various approaches to study heart cell lineage and characterization of progenitor cell types in murine NHP and human stem cell models, we can generate an atlas of cell type intermediates in the developing human heart. Through cell labeling, we will establish cell lineage in heart explants, cultured in vitro, to view how cell types relate during development. This, complemented by in vitro cardiac differentiation of human and NHP ES and iPS cells, will allow us to explore the effects on cardiac differentiation and cell lineage of patient-derived congenital heart disease mutations.
Tissue Engineering 5D Heart Patches
Our ability to purify, clone, and obtain semi continuous lines of human multipotent islet positive heart progenitors from human ES cell lines represents an opportunity to generate components from a single cell. We are examining the ability of human MICPs to generate cardiac muscle, smooth muscle, and endothelial cells in response to defined paracrine cues in reconstituted heart tissue engineered synthetic and biological matrices. Our goal is to implement this technology to clinical niches where a generated heart muscle "patch" can be utilized where advanced therapies are currently lacking. This work is supported by an ERC advanced grant No 743225.
A Novel Paradigm to Restore Gene Function
We have established a new mode of delivery, based on chemically modified mRNA, that escapes triggering innate immunity signals and allows for non-integrating, transient, and targeted expression in the intact heart and skeletal muscle; currently utilized to express VEGF in mouse models. We are building a library of stabilized mRNAs for the human "secretome" that can be tested in animal models for various disease situations, as well as in primary human cell model systems that are available at KI. This mRNA technology will help evaluate the function of known and novel paracrine and intracellular signals in developmental, physiological, regenerative, and disease related animal models (small and large) of human cardiac disease.
Katarina Drakenberg Administrative Coordinator, PhD
Christopher Yen PhD student
Trajectory mapping of human embryonic stem cell cardiogenesis reveals lineage branch points and an ISL1 progenitor-derived cardiac fibroblast lineage.
Mononen MM, Leung CY, Xu J, Chien KR
Stem Cells 2020 10;38(10):1267-1278
Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes.
Gan LM, Lagerström-Fermér M, Carlsson LG, Arfvidsson C, Egnell AC, Rudvik A, Kjaer M, Collén A, Thompson JD, Joyal J, Chialda L, Koernicke T, Fuhr R, Chien KR, Fritsche-Danielson R
Nat Commun 2019 02;10(1):871
Regenerating the field of cardiovascular cell therapy.
Chien KR, Frisén J, Fritsche-Danielson R, Melton DA, Murry CE, Weissman IL
Nat Biotechnol 2019 03;37(3):232-237
Population and Single-Cell Analysis of Human Cardiogenesis Reveals Unique LGR5 Ventricular Progenitors in Embryonic Outflow Tract.
Sahara M, Santoro F, Sohlmér J, Zhou C, Witman N, Leung CY, Mononen M, Bylund K, Gruber P, Chien KR
Dev Cell 2019 02;48(4):475-490.e7
Human ISL1+ Ventricular Progenitors Self-Assemble into an In Vivo Functional Heart Patch and Preserve Cardiac Function Post Infarction.
Foo KS, Lehtinen ML, Leung CY, Lian X, Xu J, Keung W, Geng L, Kolstad TRS, Thams S, Wong AO, Wong N, Bylund K, Zhou C, He X, Jin SB, Clarke J, Lendahl U, Li RA, Louch WE, Chien KR
Mol Ther 2018 07;26(7):1644-1659