Tatiana Kalin

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• Deng, Z., Gao, W., Kohram, F., Li, E., Kalin, T. V., Shi, D., & Kalinichenko, V. V. (2024). Fluorinated amphiphilic Poly(β-Amino ester) nanoparticle for highly efficient and specific delivery of nucleic acids to the Lung capillary endothelium. Bioactive materials, 31, 1-17.
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  Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension, viral and bacterial pneumonia, bronchopulmonary dysplasia, and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). To correct endothelial dysfunction, there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision. While several nanoparticle delivery systems targeting endothelial cells have been recently developed, none of them are specific to lung endothelial cells without targeting other organs in the body. In the present study, we successfully solved this problem by developing non-toxic poly(β-amino) ester (PBAE) nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells. After intravenous administration, the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types. IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs. Fluorination of PBAE was required for lung endothelial cell-specific targeting. Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice. Thus, fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.
• Acharya, A., Bian, F., Gomez-Arroyo, J., Wagner, K. A., Kalinichenko, V. V., & Kalin, T. V. (2023). Hypoxia represses FOXF1 in lung endothelial cells through HIF-1α. Frontiers in physiology, 14, 1309155.
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  Forkhead Box F1 (FOXF1) transcription factor plays a critical role in lung angiogenesis during embryonic development and lung repair after injury. FOXF1 expression is decreased in endothelial cells after lung injury; however, molecular mechanisms responsible for the FOXF1 transcript changes in injured lung endothelium remain unknown. We used immunostaining of injured mouse lung tissues, FACS-sorted lung endothelial cells from hypoxia-treated mice, and data from patients diagnosed with hypoxemic respiratory failure to demonstrate that hypoxia is associated with decreased FOXF1 expression. Endothelial cell cultures were used to induce hypoxia and identify the upstream molecular mechanism through which hypoxia inhibits FOXF1 gene expression. Bleomycin-induced lung injury induced hypoxia in the mouse lung tissue which was associated with decreased expression. Human mRNA was decreased in the lungs of patients diagnosed with hypoxemic respiratory failure. Mice exposed to hypoxia exhibited reduced expression in the lung tissue and FACS-sorted lung endothelial cells. , hypoxia (1% of O) or treatment with cobalt (II) chloride increased HIF-1α protein levels but inhibited expression in three endothelial cell lines. Overexpression of HIF-1α in cultured endothelial cells was sufficient to inhibit expression. siRNA-mediated depletion of HIF-1α prevented the downregulation of gene expression after hypoxia or cobalt (II) chloride treatment. Hypoxia inhibits FOXF1 expression in endothelial cells in a HIF-1α dependent manner. Our data suggest that endothelial cell-specific inhibition of HIF-1α via gene therapy can be considered to restore FOXF1 and improve lung repair in patients with severe lung injury.
• Bian, F., Lan, Y. W., Zhao, S., Deng, Z., Shukla, S., Acharya, A., Donovan, J., Le, T., Milewski, D., Bacchetta, M., Hozain, A. E., Tipograf, Y., Chen, Y. W., Xu, Y., Shi, D., Kalinichenko, V. V., & Kalin, T. V. (2023). Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling. Nature communications, 14(1), 2560.
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  Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF.
• Donovan, J., Deng, Z., Bian, F., Shukla, S., Gomez-Arroyo, J., Shi, D., Kalinichenko, V. V., & Kalin, T. V. (2023). Corrigendum: Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma the combination therapy with FOXM1 inhibitor RCM1. Frontiers in oncology, 13, 1163510.
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  [This corrects the article DOI: 10.3389/fonc.2023.1112859.].
• Donovan, J., Deng, Z., Bian, F., Shukla, S., Gomez-Arroyo, J., Shi, D., Kalinichenko, V. V., & Kalin, T. V. (2023). Improving anti-tumor efficacy of low-dose Vincristine in rhabdomyosarcoma the combination therapy with FOXM1 inhibitor RCM1. Frontiers in oncology, 13, 1112859.
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  Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NP), which efficiently delivers RCM1 to mouse RMS tumors . The combination of low doses of vincristine together with intravenous administration of NP nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified as a uniquely downregulated gene after the combination treatment. Knockdown of in RMS cells recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity.
• Kolesnichenko, O. A., Flood, H. M., Zhang, Y., Ustiyan, V., Cuervo Jimenez, H. K., Kalin, T. V., & Kalinichenko, V. V. (2023). Endothelial progenitor cells derived from embryonic stem cells prevent alveolar simplification in a murine model of bronchopulmonary dysplasia. Frontiers in cell and developmental biology, 11, 1209518.
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  Vascular remodeling and compromised alveolar development are hallmarks of chronic pulmonary diseases such as bronchopulmonary dysplasia (BPD). Despite advances in neonatal healthcare the number of BPD cases worldwide continues to increase. One approach to overcoming the premature arrest in lung development seen in BPD is to stimulate neonatal angiogenesis via delivery and engraftment of endothelial progenitor cells (EPCs). One such population is resident to the pulmonary microvasculature and expresses both FOXF1 and c-KIT. Previous studies have shown that c-KITFOXF1 EPCs are highly sensitive to elevated levels of oxygen (hyperoxia) and are decreased in premature infants with BPD and hyperoxia-induced BPD mouse models. We hypothesize that restoring EPCs through transplantation of c-KITFOXF1 EPCs derived from pluripotent embryonic stem cells (ESCs), will stimulate neonatal angiogenesis and alveolarization in mice with hyperoxia-induced lung injury. Utilizing a novel ESC line with a FOXF1:GFP reporter, we generated ESC-derived c-KITFOXF1 EPCs . Using a second ESC line which contains FOXF1:GFP and tdTomato transgenes, we differentiated ESCs towards c-KITFOXF1 EPCs and tracked them after injection into the neonatal circulation of hyperoxia-injured mice. After a recovery period in room air conditions, we analyzed c-KITFOXF1 EPC engraftment and quantified the number of resident and circulating endothelial cells, the size of alveolar spaces, and the capillary density after EPC transplantations. Herein, we demonstrate that addition of BMP9 to the directed endothelial differentiation protocol results in very efficient generation of c-KITFOXF1 EPCs from pluripotent ESCs. ESC-derived c-KITFOXF1 EPCs effectively engraft into the pulmonary microvasculature of hyperoxia-injured mice, promote vascular remodeling in alveoli, increase the number of resident and circulating endothelial cells, and improve alveolarization. Altogether, these results provide a proof-of-principle that cell therapy with ESC-derived c-KITFOXF1 EPCs can prevent alveolar simplification in a hyperoxia-induced BPD mouse model.
• Pradhan, A., Che, L., Ustiyan, V., Reza, A. A., Pek, N. M., Zhang, Y., Alber, A. B., Kalin, T. R., Wambach, J. A., Gu, M., Kotton, D. N., Siefert, M. E., Ziady, A. G., Kalin, T. V., & Kalinichenko, V. V. (2023). Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia. American journal of respiratory and critical care medicine, 207(8), 1042-1054.
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  Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is linked to heterozygous mutations in the (Forkhead Box F1) gene, a key transcriptional regulator of pulmonary vascular development. There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed. Identify-small molecule compounds that stimulate FOXF1 signaling. We used mass spectrometry, immunoprecipitation, and the ubiquitination assay to identify TanFe (transcellular activator of nuclear FOXF1 expression), a small-molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and acute lung injury and in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV. We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1-HECTD1 protein-protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cells . TanFe increased protein concentrations of FOXF1 and its target genes , , and in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein concentrations in lungs of embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality of mice after birth. TanFe increased angiogenesis in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV with deletion. TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.
• Shukla, S., Saha, T., Rama, N., Acharya, A., Le, T., Bian, F., Donovan, J., Tan, L. A., Vatner, R., Kalinichenko, V., Mascia, A., Perentesis, J. P., & Kalin, T. V. (2023). Ultra-high dose-rate proton FLASH improves tumor control. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 186, 109741.
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  Proton radiotherapy (PRT) offers potential benefits over other radiation modalities, including photon and electron radiotherapy. Increasing the rate at which proton radiation is delivered may provide a therapeutic advantage. Here, we compared the efficacy of conventional proton therapy (CONV) to ultrahigh dose-rate proton therapy, FLASH, in a mouse model of non-small cell lung cancers (NSCLC).