Harald Lahm
Technische Universität München, Department of Cardiovascular Surgery, Department Member
Research Interests:
Research Interests:
Research Interests:
Introduction: The existence of activated cardiac resident stem cells after myocardial infarction (MI) is still subject of controversial discussion. Hypothesis: We hypothesized that the adult mammal...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
ZusammenfassungIschämische Herzerkrankungen zählen weltweit weiterhin zu den führenden Todesursachen. Akute und chronische Myokardischämien ziehen einen Verlust an funktionellem Myokard nach sich und sind mit weitreichenden strukturellen... more
ZusammenfassungIschämische Herzerkrankungen zählen weltweit weiterhin zu den führenden Todesursachen. Akute und chronische Myokardischämien ziehen einen Verlust an funktionellem Myokard nach sich und sind mit weitreichenden strukturellen Umbauprozessen am verbleibenden Myokard assoziiert. Häufig entwickelt sich eine progrediente Herzinsuffizienz. Aus Ermangelung kurativer Therapieoptionen bei Vorliegen einer chronischen Herzinsuffizienz besteht, insbesondere aufgrund der limitierten Zahl transplantierbarer Spenderorgane, dringender Bedarf für alternative Behandlungsansätze. Vielversprechend erscheint das innovative therapeutische Konzept der zellbasierten myokardialen Regeneration, das zum Ziel hat, über eine Applikation oder eine Stimulation von Stamm- und Progenitorzellen verloren gegangene Herzmuskelzellen funktionell zu ersetzen bzw. die Formation neuer Gefäße im geschädigten Herzmuskel zu bewirken. Entgegen der früheren Lehrmeinung verfügt das adulte Herz über gewisse endogene Regenerationskapazitäten, wie sie bei niederen Vertebraten bereits seit Längerem bekannt sind. Intrinsische Regenerationsvorgänge werden durch die Proliferation präexistenter Kardiomyozyten und/oder residenter Stammzellen vermittelt; die hierfür verantwortlichen Mechanismen sind jedoch noch weitestgehend unverstanden. Transgene Tiermodelle eröffnen wichtige Erkenntnisse zum Verständnis dieser Prozesse und liefern möglicherweise entscheidende Hinweise für spezifische Therapieansätze. Dieser Beitrag fasst die wichtigsten aktuellen Erkenntnisse zum Thema endogener, kardialer Regenerationsvorgänge zusammen und gibt eine Übersicht über die Prinzipien des „lineage tracing“ sowie „fate mapping“ als molekularbiologische Methoden der Wahl bei der Aufklärung solcher u. U. therapeutisch beeinflussbarer Prozesse.AbstractIschemic heart disease and its sequelae are still among the leading causes of death worldwide. Myocardial infarction causes a major loss of functional contractile myocardium and is subsequently associated with extensive structural remodeling of the remaining myocardium. Progressive congestive heart failure often ensues. In the absence of curative therapy options, especially due to the limited number of transplantable donor organs, alternative treatment strategies are urgently needed. The innovative therapeutic concept of cell-based myocardial regeneration aims to functionally replace lost myocardium by application or stimulation of stem and progenitor cells and to stimulate the formation of new blood vessels within damaged heart muscle. For many decades the adult mammalian heart has been considered a terminally differentiated organ without any intrinsic capacity for regeneration. Contrary to this past doctrine recent studies have demonstrated a limited capacity of the postnatal mammalian heart to undergo cardiomyocyte renewal. This process may be mediated by cardiomyocytes reentering the cell cycle and/or by resident progenitor cells; however, the cellular mechanisms for this endogenous regenerative capacity are still barely understood. Transgenic animal models offer important insights into the understanding of these processes and may provide important hints for the development of specific therapeutic approaches. This article gives an overview about the most important recent findings on the subject of endogenous cardiac regeneration along with a brief overview of the principles of the lineage tracing and fate mapping techniques as molecular biological methods of choice in the investigation of such potentially therapeutically modifiable processes.
Research Interests: Medicine and Gynecology
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Endocrinology, Genetics, Biology, Medicine, Biological Sciences, and 15 moreGrowth Hormone, Growth, Internal Medicine, Kidney, Liver, Female, Animals, Body Weight, Abdominal Fat, Growth Inhibition, Growth Factor, Insulin Like Growth Factor, Body Weight Gain, Medical and Health Sciences, and Growth Regulator
Research Interests:
Genome editing is a powerful tool to study the function of specific genes and proteins important for development or disease. Recent technologies, especially CRISPR/Cas9 which is characterized by convenient handling and high precision,... more
Genome editing is a powerful tool to study the function of specific genes and proteins important for development or disease. Recent technologies, especially CRISPR/Cas9 which is characterized by convenient handling and high precision, revolutionized the field of genome editing. Such tools have enormous potential for basic science as well as for regenerative medicine. Nevertheless, there are still several hurdles that have to be overcome, but patient-tailored therapies, termed precision medicine, seem to be within reach. In this review, we focus on the achievements and limitations of genome editing in the cardiovascular field. We explore different areas of cardiac research and highlight the most important developments: (1) the potential of genome editing in human pluripotent stem cells in basic research for disease modelling, drug screening, or reprogramming approaches and (2) the potential and remaining challenges of genome editing for regenerative therapies. Finally, we discuss soc...
Research Interests:
Pulsatile ex vivo perfusion of human saphenous vein grafts under controlled pressure conditions increases MMP-2 expression
Research Interests:
This article cites 172 articles, 89 of which you can access for free at:
Lehrstuhl für Molekulare Tierzucht und Biotechnologie/Genzentrum, 81377 München, Germany [A. H., R. R., H. L., E. W.]; Universitätskinderklinik Leipzig, 04317 Leipzig, Germany [W. K.]; Eli Lilly and Company, 61350 Bad Homburg, Germany [W.... more
Lehrstuhl für Molekulare Tierzucht und Biotechnologie/Genzentrum, 81377 München, Germany [A. H., R. R., H. L., E. W.]; Universitätskinderklinik Leipzig, 04317 Leipzig, Germany [W. K.]; Eli Lilly and Company, 61350 Bad Homburg, Germany [W. F. B.]; Institut für Klinische Chemie, Städtisches Krankenhaus München-Harlaching, 81545 München, Germany [H. J. K.]; and Endokrinologisches Labor, Lehrstuhl II für Innere Medizin, Universität Köln-Merheim, 51109 Köln, Germany [M. M. W.]
Research Interests: Cognition, Cancer, Biomarkers, Biology, Cell Division, and 15 moreHippocampus, Cell line, Female, Animals, Apolipoprotein E, Clinical Sciences, Aged, Benign Prostatic Hyperplasia, Age Factors, Cell Proliferation, Clinical Endocrinology, Alzheimer Disease, Benign Prostate Hyperplasia, Biochemistry and cell biology, and Functional Laterality
Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract... more
Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. Methods: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent–offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. Results: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients wit...
Research Interests:
Research Interests:
Acute type A aortic dissection (ATAAD) constitutes a life-threatening aortic pathology with significant morbidity and mortality. Without surgical intervention the usual mortality rate averages between 1 and 2% per hour. Thus, an early... more
Acute type A aortic dissection (ATAAD) constitutes a life-threatening aortic pathology with significant morbidity and mortality. Without surgical intervention the usual mortality rate averages between 1 and 2% per hour. Thus, an early diagnosis of ATAAD is of pivotal importance to direct the affected patients to the appropriate treatment. Preceding tests to find an appropriate biomarker showed among others an increased aggrecan (ACAN) mRNA expression in aortic tissue of ATAAD patients. As a consequence, we investigated whether ACAN is a potential biomarker for diagnosing ATAAD. Mean ACAN protein concentration showed a significantly higher plasma concentration in ATAAD patients (38.59 ng/mL, n = 33) compared to plasma of patients with thoracic aortic aneurysms (4.45 ng/mL, n = 13), patients with myocardial infarction (11.77 ng/mL, n = 18) and healthy volunteers (8.05 ng/mL, n = 12). Cardiac enzymes like creatine kinase MB and cardiac troponin T showed no correlation with ACAN levels ...
Research Interests:
MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5... more
MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte mark...
Research Interests:
Research Interests:
Research Interests:
The heart is a central human organ and its diseases are the leading cause of death worldwide, but an in-depth knowledge of the identity and quantity of its constituent proteins is still lacking. Here, we determine the healthy human heart... more
The heart is a central human organ and its diseases are the leading cause of death worldwide, but an in-depth knowledge of the identity and quantity of its constituent proteins is still lacking. Here, we determine the healthy human heart proteome by measuring 16 anatomical regions and three major cardiac cell types by high-resolution mass spectrometry-based proteomics. From low microgram sample amounts, we quantify over 10,700 proteins in this high dynamic range tissue. We combine copy numbers per cell with protein organellar assignments to build a model of the heart proteome at the subcellular level. Analysis of cardiac fibroblasts identifies cellular receptors as potential cell surface markers. Application of our heart map to atrial fibrillation reveals individually distinct mitochondrial dysfunctions. The heart map is available at maxqb.biochem.mpg.de as a resource for future analyses of normal heart function and disease.
Research Interests:
Research Interests:
Purposeγ-Catenin is a protein closely related to β-catenin. While the overexpression of β-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been... more
Purposeγ-Catenin is a protein closely related to β-catenin. While the overexpression of β-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells.Methodsγ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model.Resultsγ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule β-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo.ConclusionsThis is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.
Research Interests:
Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also... more
Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells coexpressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3(+)CD20(+) T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8(+) and CD45RO(+) memory cells and in CCR7(-) cells. Functionally, they show a higher frequency of IL-4-...
Research Interests:
Research Interests:
Research Interests:
Current rodent animal models enable the investigation of fundamental biological questions of the dynamic process of lung cancer development and progression. Specific models exist to search for the effect of genetic alterations or to test... more
Current rodent animal models enable the investigation of fundamental biological questions of the dynamic process of lung cancer development and progression. Specific models exist to search for the effect of genetic alterations or to test for the efficiency of a therapeutic regimen. Often, the optimum individual treatment is not given due to a lack of information. Molecular taxonomy of lung cancer patients has started to identify novel biological subgroups, which might be suitable for a certain therapy.
Research Interests:
Research Interests:
The generation of induced pluripotent stem (iPS) cells has successfully been achieved in many species. However, the identification of truly reprogrammed iPS cells still remains laborious and the detection of pluripotency markers requires... more
The generation of induced pluripotent stem (iPS) cells has successfully been achieved in many species. However, the identification of truly reprogrammed iPS cells still remains laborious and the detection of pluripotency markers requires fixation of cells in most cases. Here, we report an approach with nanoparticles carrying Cy3-labeled sense oligonucleotide reporter strands coupled to gold-particles. These molecules are directly added to cultured cells without any manipulation and gene expression is evaluated microscopically after overnight incubation. To simultaneously detect gene expression in different species, probe sequences were chosen according to interspecies homology. With a common target-specific probe we could successfully demonstrate expression of the GAPDH house-keeping gene in somatic cells and expression of the pluripotency markers NANOG and GDF3 in embryonic stem cells and iPS cells of murine, human, and porcine origin. The population of target gene positive cells c...