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In vivo generation of post-infarct human cardiac muscle by laminin-promoted cardiovascular progenitors [LN-521 or LN-521+LN-221]

ABSTRACT: Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical quality stem-cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein, and showed that LN-221 promotes differentiation of pluripotent hESCs towards cardiomyocyte lineage and downregulates pluripotency and teratoma associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. We show high reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from different hESC lines. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical quality cells for use in regenerative cardiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101076 | GEO | 2019/04/26

REPOSITORIES: GEO

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In vivo generation of post-infarct human cardiac muscle by laminin-promoted cardiovascular progenitors [H1 differentiation protocol]

Project description:Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical quality stem-cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein, and showed that LN-221 promotes differentiation of pluripotent hESCs towards cardiomyocyte lineage and downregulates pluripotency and teratoma associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. We show high reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from different hESC lines. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical quality cells for use in regenerative cardiology.

2019-04-26 | GSE101132 | GEO

In vivo generation of post-infarct human cardiac muscle by laminin-promoted cardiovascular progenitors [HS1001 differentiation protocol]

2019-04-26 | GSE100722 | GEO

Single-cell RNA-seq of human cardiovascular progenitor cells generated with a chemically defined, xeno-free laminin based differentiation protocol

Project description:Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical quality stem-cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein, and showed that LN-221 promotes differentiation of pluripotent hESCs towards cardiomyocyte lineage and downregulates pluripotency and teratoma associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical quality cells for use in regenerative cardiology.

2019-03-20 | GSE127955 | GEO

In vivo generation of post-infarct human cardiac muscle by laminin-promoted cardiovascular progenitors

Project description:This SuperSeries is composed of the SubSeries listed below and contains: bulk RNA-seq of two time series of a xeno-free human cardiomyocyte differentiation protocol starting from HS1001 and H1 hECSs until day 94 cardiomyocytes, single cell sequencing of cardiovascular progenitors (H1 and HS1001-derived cardiovascular progenitors at day 9 and 11) and bulk RNA-Seq of H1 hECSs that have been transferred to a LN-221 matrix. Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical quality stem-cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein, and showed that LN-221 promotes differentiation of pluripotent hESCs towards cardiomyocyte lineage and downregulates pluripotency and teratoma associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. We show high reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from different hESC lines. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical quality cells for use in regenerative cardiology.

2019-03-21 | GSE100725 | GEO

Cardiovascular progenitors regenerate infarcted swine hearts

Project description:Stem cell-derived products could replace damaged heart muscle in regenerative cardiology. Here, human embryonic stem cells (hESCs) were differentiated on laminin 521+221 to cardiovascular progenitors (CVPs). The CVPs were transplanted into the infarcted region of 10 pigs and maintained for 4- and 12- weeks. Immunohistology analyses revealed in vivo engraftment and maturation of the CVPs into cardiomyocytes (CMs). Furthermore, heart function was analyzed by magnetic resonance imaging (MRI). We observed significant improvement in the left ventricular ejection fraction (DLVEF: 21.9 ± 1.6 %, at 12-weeks), ventricular wall thickness and wall motion, as well as a reduction in infarction size after CVP transplantation as compared to control pigs (p-value < 0.05). There are temporary episodes of ventricular tachyarrhythmia (VT) in four pigs and one pig had persistent VT. On the other hand, the remaining 5 pigs remained in normal sinus rhythm. Importantly, all pigs survived without any VT-related death, suggesting the potential for developing CVPs towards applications in regenerative cardiology.

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Long-term expansion of functional pancreatic islets on a laminin-521 matrix and curative transplantation into diabetic mice

Project description:In this study we show, for the first time, that whole islets can be cultured and significantly expanded long-term in vitro on specific basement membrane (BM) laminin LN-521 which is a normal component of islet BMs. Isolated islets adhere and flatten to form 2-3 cell layer entities with ~10 % of all endocrine cell types proliferating after 2-5 weeks in culture. Time-lapse imaging of freshly isolated islets in suspension labeled with hypoxia and DNA degradation indicators reveals that spherical islets on LN-111 rapidly develop hypoxia and central necrosis, in contrast to islets attached to LN-521, which normal b-cell glucose responsiveness. RNA sequencing analyses reveal that freshly isolated islets express LN-521 binding integrins. Compared to other matrices, islets grown on LN-521 develop a unique expression signature, including expression of specific integrins, involved in cell adhesion and matrix production as well as proliferation. The results reveal specific LN-521-mediated effects into islet cells and suggest that use of in vitro expanded islets may significantly enhance the efficacy of islet transplantation treatment of T1D.

2018-11-09 | GSE89677 | GEO

aCGH study of invasive duct carcinoma (IDC) of the breast without axillary lymph node LN and with sentinel LN metastasis

Project description:22 patients with IDC: 8 without LN metastases (IDC) and 14 with sentinel LN metastases (IDCM). Sampling was limited to 29 paraffin blocks which could be used up without interference with diagnostic procedures: 8 IDCs, 11 IDCMs and 10 ipsilateral LN metastases [5 to the sentinel LN (first in lymph drainage chain, MS) and 5 to more distal (MD)]. 7 IDCMs had samples of their LN metastases (IDCM9,13, 14, 15, 17, 18, 19). 3 samples of metastases (MS20, 21, 22) did not have paired primary IDCM samples and 4 IDCMs (IDCM10, 11, 12, 16) did not have samples of their LN metastases. Keywords: Comparative clinical study

2009-02-01 | GSE10600 | GEO

LN immunoinfiltrate analysis

Project description:LN immunoinfiltrate analysis

| PRJNA634254 | ENA

Homo sapiens

Project description:In vivo generation of post-infarct human cardiac muscle by laminin-promoted cardiovascular progenitors [LN-521 or LN-521+LN-221]

| PRJNA393685 | ENA

Xeno-free and Chemically Defined Human System for Culturing Human Epidermal Keratinocytes

Project description:Developing an effective xeno-free and defined system for human keratinocyte culture has been one of the fundamental measures in current cellular therapy. For keratinocytes, in particular, such system will not only fulfill clinical safety and quality criteria, it will allow for the management of less severe burns and other skin injuries such as chronic wounds. To date, the expansion of autologous keratinocytes in the clinical settings still relies on 3T3 feeder co-culture system. Here we report a completely xeno-free and defined culture system by using human recombinant laminins as feeder replacement. We have thoroughly characterized the cells cultured in this new system both in vitro and in vivo. We found that laminin-511/-521, and the unanticipated laminin-411/-421, but not -332, -111, -121, -211, or LN-221 support adult human skin keratinocytes and could maintain their self-renewal properties comparable to the 3T3 system. We believe our new culture method should facilitate broader use of cultured epithelial cell products for today’s regenerative medicine.

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