Nico Lachmann

Nico Lachmann
Hannover Medical School | MHH · Department of Pediatric Pneumology, Allergology and Neonatology

PhD

About

119
Publications
11,562
Reads
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1,596
Citations
Additional affiliations
September 2020 - present
Hannover Medical School
Position
  • Principal Investigator
Description
  • https://www.mhh.de/institute-zentren-forschungseinrichtungen/institut-fuer-experimentelle-haematologie/employees/nico-lachmann/ag-lachmann/hauptseite
June 2015 - August 2020
Hannover Medical School
Position
  • Group Leader
December 2013 - December 2019
Cincinnati Children's Hospital Medical Center
Position
  • Instructor

Publications

Publications (119)
Article
Rationale: Although the transplantation of induced pluripotent stem cell (iPSC)-derived cells harbors enormous potential for the treatment of pulmonary diseases, in vivo data demonstrating clear therapeutic benefits of human iPSC-derived cells in lung disease models are missing. Objectives: We have tested the therapeutic potential of iPSC-derive...
Article
Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1orIFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon γ (IFN-...
Article
Full-text available
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNγ) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNγ is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous a...
Article
Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granul...
Article
Macrophages can be found in various tissues and play an important role in organ function by sensing and eradicating pathogens, regulating immune responses and contributing to tissue homeostasis and repair. Nowadays, increasing numbers of macrophage-based cell therapies are entering (pre-) clinical studies e.g. for the treatment of liver cirrhosis....
Article
Drug-inducible suicide systems may help to minimize risks of human induced pluripotent stem cell (hiPSC) therapies. Recent research challenged the usefulness of such systems since rare drug-resistant subclones were observed. We have introduced a drug-inducible Caspase9 suicide system (iCASP9) into the AAVS1 safe harbor locus of hiPSCs. In these cel...
Article
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Chimeric antigen receptor (CAR) T-cell therapies have shown impressive results in patients with hematological malignancies; however, little success has been achieved in the treatment of solid tumors. Recently, macrophages (MΦs) were identified as an additional candidate for the CAR approach, and initial proof of concept studies using peripheral blo...
Article
Macrophages derived from human induced pluripotent stem cells (iPSCs) have the potential to enable the development of cell-based therapies for numerous disease conditions. We here provide a detailed protocol for the mass production of iPSC-derived macrophages (iPSC-Mac) in scalable suspension culture on an orbital shaker or in stirred-tank bioreact...
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Primary or secondary immunodeficiencies are characterized by disruption of the cellular and humoral immunity. Respiratory infections are a major cause of morbidity and mortality among immunodeficient or immunocompromised patients with Staphylococcus aureus being a common offending organism. We here propose an adoptive macrophage transfer approach a...
Preprint
Full-text available
Drug-inducible suicide systems may help to minimize risks of cellular therapies due to the tumor forming potential of human induced pluripotent stem cells (hiPSCs). Recent research challenged the usefulness of such systems since rare drug-resistant subclones were observed that showed elimination or silencing of the transgene. We have introduced a d...
Article
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Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack o...
Article
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The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrat...
Article
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Humanized mouse models generated with human hematopoietic stem cells (HSCs) and reconstituting the human immune system (HIS-mice) are invigorating preclinical testing of vaccines and immunotherapies. We have recently shown that human engineered dendritic cells boosted bonafide human T and B cell maturation and antigen-specific responses in HIS-mice...
Article
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Recent understanding of the role and contribution of immune cells in disease onset and progression has pioneered the field of immunotherapies. Use of genetic engineering to deliver, correct or enhance immune cells has been clinically successful, especially in the field of cancer immunotherapy. Indeed, one of the most attractive approaches is the in...
Article
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Inherited deficiency of the antiprotease alpha-1 antitrypsin (AAT) is associated with liver failure and early-onset emphysema. In mice, in vivo lentiviral transduction of alveolar macrophages (AMs) has been described to yield protective pulmonary AAT levels and ameliorate emphysema development. We here investigated the pulmonary transplantation of...
Article
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Induced pluripotent stem cell (iPSC)-derived cell products hold great promise as a potential cell source in personalized medicine. As concerns about the potential risk of graft-related severe adverse events, such as tumor formation from residual pluripotent cells, currently restrict their applicability, we established an optimized tool for therapeu...
Article
Severe congenital neutropenia (CN) is a pre-leukemic bone marrow failure syndrome that can evolve to acute myeloid leukemia (AML). Mutations in CSF3R and RUNX1 are frequently observed in CN patients, although how they drive the transition from CN to AML (CN/AML) is unclear. Here we establish a model of stepwise leukemogenesis in CN/AML using CRISPR...
Article
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Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macropha...
Article
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Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC l...
Article
Full-text available
Macrophages are unique cells of the innate immunity and can be found in various tissues (tissue resident macrophages; TRMs). Macrophages and TRMs play a pivotal role in tissue homeostasis and can contribute to the onset and progression of certain diseases. We and others have developed macrophage-based cellular immunotherapies and explored the field...
Article
Background and aims: Mutations in IL10 or the IL10-receptor lead to very early onset (VEO) inflammatory bowel disease (IBD), a life-threatening disease which is often unresponsive to conventional medication. Recent studies have demonstrated that defective IL-10 receptor signaling in innate immune cells is a key driver of severe intestinal inflamma...
Article
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Inherited defects in MyD88 and IRAK4, two regulators in Toll-like receptor (TLR) signaling, are clinically highly relevant, but still incompletely understood. MyD88- and IRAK4-deficient patients are exceedingly susceptible to a narrow spectrum of pathogens, with ∼50% lethality in the first years of life. To better understand the underlying molecula...
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Antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, are important regulators of the immune system, as they connect the innate and adaptive immunity by critically regulating T-cell responses. Thus, APCs are involved in both tissue homeostasis and tolerance, but also coordinate immune responses in case of infection and inf...
Article
Cystic fibrosis is caused by mutations in the CFTR gene, which lead to impaired ion transport in epithelial cells. Although lung failure due to chronic infection is the major comorbidity in individuals with cystic fibrosis, the role of CFTR in non-epithelial cells has not been definitely resolved. Given the important role of host defense cells, we...
Article
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Induced pluripotent stem cells (iPSCs) from patients with genetic disorders are a valuable source for in vitro disease models, which enable drug testing and validation of gene and cell therapies. We generated iPSCs from a severe congenital neutropenia (SCN) patient, who presented with a nonsense mutation in the glucose-6-phosphatase catalytic subun...
Article
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Cyclin O (CCNO) is involved in cell cycle regulation and mutations of CCNO are linked to the rare genetic disease primary ciliary dyskinesia (PCD). Mutations in CCNO are associated with reduced cilia number and cilia agenesis on epithelia of the respiratory tract. This article deals with the description of two hiPSC lines generated from a PCD patie...
Article
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Dynein axonemal heavy chain 5 (DNAH5) is part of a microtubule-associated protein complex found within the cilia of the lung. Mutations in the DNAH5 gene lead to impaired ciliary function and are linked to primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder. We established two human induced pluripotent stem cell (hiPSC) lines gene...
Article
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Hematopoietic development is spatiotemporally tightly regulated by defined cell-intrinsic and extrinsic modifiers. The role of cytokines has been intensively studied in adult hematopoiesis; however, their role in embryonic hematopoietic specification remains largely unexplored. Here, we used induced pluripotent stem cell (iPSC) technology and estab...
Article
Full-text available
Induced pluripotent stem cells (iPSCs) offer great promise for the field of regenerative medicine, and iPSC-derived cells have already been applied in clinical practice. However, potential contamination of effector cells with residual pluripotent cells (e.g., teratoma-initiating cells) or effector cell-associated side effects may limit this approac...
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Cystic Fibrosis (CF) is a genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which encodes for a chloride ion channel regulating the balance of salt and water across secretory epithelia. Here we generated an iPSC line from a CF patient homozygous for the p.Asn1303Lys mutation, a Class II foldi...
Article
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Autosomal recessive (AR) complete interferon γ receptor 1 (IFN-γR1) deficiency, also known as one genetic etiology of Mendelian Susceptibility to Mycobacterial Disease (MSMD), is a life-threatening congenital disease leading to premature death. Affected patients present a pathognomonic predisposition to recurrent and severe infections with environm...
Article
Full-text available
Interferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients wit...
Article
Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by a genetic predisposition for thoracic aortic aneurysm and dissection. Despite heterozygous loss-of-function mutations in genes for ligand, receptor, or downstream mediators of the transforming growth factor β (TGFβ) pathway, LDS is associated with a signature of high T...
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Chronic mucocutaneous candidiasis (CMC) is a disease that is characterized by susceptibility to chronic or recurrent infections with Candida spp. due to mutations affecting mainly the IL-17 signaling of T-Cells. The most common etiologies of CMC are gain-of-function (GOF) mutations in the STAT1 gene. In this paper we report the generation of a hiPS...
Article
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Infections with Mycobacterium tuberculosis (Mtb) are still among the top 10 causes of death worldwide, highlighting the utmost need for new forms of medical treatments. In this issue of Stem Cell Reports, Han et al. (2019) describe a technique to screen therapeutically active compounds targeting Mtb using pluripotent stem cell-derived macrophages....
Article
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Red blood cell (RBC) differentiation from human induced pluripotent stem cells (hiPSCs) offers great potential for developmental studies and innovative therapies. However, ex vivo erythropoiesis from hiPSCs is currently limited by low efficiency and unphysiological conditions of common culture systems. Especially the absence of a physiological nich...
Article
Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic ste...
Article
Full-text available
Hereditary pulmonary alveolar proteinosis (PAP) is a genetic lung disease characterized by surfactant accumulation and respiratory failure arising from disruption of GM-CSF signaling. While mutations in either CSF2RA or CSF2RB (encoding GM-CSF receptor α or β chains, respectively) can cause PAP, α chain mutations are responsible in most patients. P...
Article
We describe the establishment of an embryoid-body-based protocol for hematopoietic/myeloid differentiation of human induced pluripotent stem cells that allows the generation of CD34⁺ cells or mature myeloid cells in vitro. Using this model, we were able to recapitulate the defective granulocytic differentiation in patients with severe congenital ne...
Article
Full-text available
Since their discovery in 2006, induced pluripotent stem cells (iPSCs) have opened up a world of possibilities for regenerative medicine and novel cell-based therapeutics. Now, over a decade later, robust reprogramming and expansion and differentiation protocols have been developed, and iPSC-derived cells have been used in a wide variety of small an...
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Full-text available
The increasing number of severe infections with multi-drug-resistant pathogens worldwide highlights the need for alternative treatment options. Given the pivotal role of phagocytes and especially alveolar macrophages in pulmonary immunity, we introduce a new, cell-based treatment strategy to target bacterial airway infections. Here we show that the...
Article
Full-text available
Macrophages are key cells of the innate immune system and act as tissue resident macrophages (TRMs) in the homeostasis of various tissues. Given their unique functions and therapeutic use as well as the feasibility to derive macrophages in vitro from hematopoietic stem cell (HSC) sources, we propose an “easy-to-use” immune cell spray (ICS) formulat...
Article
Full-text available
Induced pluripotent stem cell (iPSC)-derived hematopoietic cells represent a highly attractive source for cell and gene therapy. Given the longevity, plasticity, and self-renewal potential of distinct macrophage subpopulations, iPSC-derived macrophages (iPSC-Mφ) appear of particular interest in this context. We here evaluated the airway residence,...
Article
Full-text available
Suppression of therapeutic transgene expression from retroviral gene therapy vectors by epigenetic defence mechanisms represents a problem that is particularly encountered in pluripotent stem cells (PSCs) and their differentiated progeny. Transgene expression in these cells, however, can be stabilised by CpG-rich ubiquitous chromatin opening elemen...
Article
Full-text available
Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As...
Article
Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder of pulmonary surfactant accumulation and hypoxemic respiratory failure caused by mutations in CSF2RA (encoding the granulocyte/macrophage-colony stimulating factor (GM-CSF) receptor α-chain (CD116)), which results in reduced GM-CSF-dependent pulmonary surfactant clearance by alveol...