Biomedical subjects

Bumsoo Han

Publications and source records attributed to Bumsoo Han.

7 recordsLinked to original sources

PubMed2026

Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma with context-dependent tumor-restraining and tumor-promoting functions, highlighting the need to selectively reprogram stromal states. Extravascular coagulation is a prominent feature of the PDAC tumor microenvironment, yet whether it functions as an upstream regulator of fibrotic stromal states, rather than merely a byproduct of tumor-associated vascular dysfunction, has remained unclear. Here, we identify extravascular coagulation as a tumor-amplified regulatory module that stabilizes pro-fibrotic stromal states via tumor-intrinsic protease-activated receptor-1 (PAR1) signaling. To interrogate this axis mechanistically, we integrated human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models that reconstruct tumor-stroma interactions under controlled coagulation exposure, followed by cross-scale validation in vivo. Analysis of The Cancer Genome Atlas (TCGA) revealed heterogeneous F2R (PAR1) expression across tumors, with elevated expression associated with fibrotic transcriptional programs and reduced survival. Consistently, thrombin induced coordinated pro-fibrotic programs in tumor cells and cancer-associated fibroblasts (CAFs), which were recapitulated in MPTS where tumor-intrinsic PAR1 was required for amplification of extracellular matrix deposition and CAF activation. Mechanistically, PAR1 signaling amplified tumor-stroma communication, in part through induction of TGF-β1-dependent pathways, establishing a reinforcing feedback loop that stabilizes fibrotic remodeling. Pharmacologic inhibition of PAR1 selectively suppressed the fibrotic transcriptional program within myofibroblastic CAFs while reducing the abundance of other CAF subtypes, reprogramming stromal states and attenuating tumor progression across MPTS and in vivo models. These findings establish a coagulation-PAR1 axis as an upstream organizer of PDAC stromal architecture and identify pharmacologic PAR1 inhibition as a mechanistically grounded strategy for selectively reprogramming the tumor-promoting stroma.

Journal Article↗

PubMed2025

Interrogating functional connectivity of in vitro neural glia tissue model modulated through integrative control of matrix stiffness and a neurotrophic factor.

Brain function emerges from intricate cellular communication within neural networks. Both In silico neuronal models and primary neuron cells have revealed that the branching architecture of individual neurons determines the bioelectrical signal propagation pattern and dynamics. However, whether stem cell-differentiated neurons can build functional connectivity regulated by neuronal morphology has yet to be determined. Here, we hypothesized that neurite length, branching, or both factors would regulate the functional connectivity of the stem cell-differentiated neural network. We examined this hypothesis by differentiating mouse cortical neural stem cells (NSCs) on Matrigel substrates with varying storage moduli, both with and without basic fibroblast growth factor (bFGF). Interestingly, with bFGF, Matrigel with a storage modulus (G') of 100 Pa drives NSCs to differentiate into neurons with more dendritic branches, while the gel with G' of 50 Pa led to the development of longer neurites with fewer branches. Notably, branch-rich neural networks exhibited an increased frequency of calcium transients. Using a MATLAB-based analysis pipeline incorporating graph theory, we constructed spatial and temporal calcium activity maps, revealing that branching complexity, more than neurite length, correlates with the density and strength of functional neural circuits. Overall, this study demonstrates that the dendritic branching of neurons, modulated with matrix stiffness and neurotrophic factors, is a key element in enhancing the electrophysiological functionality of the stem cell-differentiated neural network. This finding will have a significant impact on efforts to reconstruct functional neural tissue models, advancing both regenerative therapies and unexplored applications, including biological computing.

Animals↗

PubMed2005

A quantitative analysis on latent heat of an aqueous binary mixture.

The latent heat during phase change of water-NaCl binary mixture was measured using a differential scanning calorimeter, and the magnitude for two distinct phase change events, water/ice and eutectic phase change, were analyzed considering the phase change characteristics of a binary mixture. During the analysis, the latent heat associated with each event was calculated by normalizing the amount of each endothermic peak with only the amount of sample participating in each event estimated from the lever rule for the phase diagram. The resulting latent heat of each phase change measured is 303.7 +/- 2.5 J/g for water/ice phase change, and 233.0 +/- 1.6 J/g for eutectic phase change, respectively regardless of the initial concentration of mixture. Although the latent heats of water/ice phase change in water-NaCl mixtures are closely correlated, further study is warranted to investigate the reason for smaller latent heat of water/ice phase change than that in pure water (335 J/g). The analysis using the lever rule was extended to estimate the latent heat of dihydrate as 115 J/g with the measured eutectic and water/ice latent heat values. This new analysis based on the lever rule will be useful to estimate the latent heat of water-NaCl mixtures at various concentrations, and may become a framework for more general analysis of latent heat of various biological solutions.

Calorimetry, Differential Scanning↗

PubMed2005

A cryoinjury model using engineered tissue equivalents for cryosurgical applications.

Cryosurgery is emerging as a promising treatment modality for various cancers, but there are still challenges to be addressed to improve its efficacy. Two primary challenges are determining thermal injury thresholds for various types of cell/tissue, and understanding of the mechanisms of freezing induced cell/tissue injury within a cryolesion. To address these challenges, various model systems ranging from cell suspensions to three-dimensional in vivo tissues have been developed and used. However, these models are either oversimplifications of in vivo tissues or difficult to control and extract precise experimental conditions from. Therefore, a more readily controllable model system with tissue-like characteristics is needed. In this study, a cryoinjury model was developed using tissue engineering technology, and the capabilities of the model were demonstrated. Engineered tissue equivalents (TEs) were constructed by seeding and culturing cells in a type I collagen matrix. Two different cell lines were used in this study, AT-1 rat prostate tumor cells and LNCaP human prostate cancer cells. The constructed TEs underwent a freeze/thaw cycle imitating in vivo cryosurgery. Thermal conditions within TEs during freeze/thaw cycles were characterized, and the responses of TEs to these thermal conditions including freezing induced cellular injury and extracellular matrix damage were investigated at three different time points. The results illustrate the feasibility to establish thermal thresholds of cryoinjury for different cell/tissue types using the presently developed model, and its potential capabilities to study cell death mechanisms, cell proliferation or migration, and extracellular matrix structural damage after a freeze/thaw cycle.

Animals↗

PubMed2004

Direct cell injury associated with eutectic crystallization during freezing.

Freezing induced direct cell injury has been explained by a two-factor hypothesis-intracellular ice formation (IIF) at rapid cooling rates, and solution effects at slow cooling rates. Even though IIF is generally believed to be a major injury mechanism at rapid cooling rates, injury by solution effects is not fully understood and several injury mechanisms have been suggested. Solution effects have generally been considered the result of the elevated electrolyte concentration within the intracellular and extracellular space during freezing. In addition to the injury by this elevated electrolyte concentration, freezing injury associated with eutectic crystallization was investigated. To examine the injury associated with eutectic crystallization, two different experiments were designed and performed. In the first experiment, two groups of AT-1 rat prostate tumor cell suspensions were frozen and thawed on a cryomicroscope in the same way except that eutectic crystallization was initiated in only one group. During the second experiment, AT-1 cells were suspended in several different media, which have different eutectic crystallization temperatures, and exposed to a single cooling-warming cycle with varying end temperature of the protocol on a directional solidification stage. After both experiments, post-thaw viability was evaluated and compared. The post-thaw viability drops significantly upon the occurrence of the eutectic crystallization regardless of suspending media, which suggests direct cell injury associated with eutectic crystallization. Based on these observations, two possible injury mechanisms are anticipated: (i) mechanical damage to the cell membrane due to eutectic crystallization, and (ii) intracellular eutectic formation (IEF). The proposed mechanisms provide a more comprehensive physical explanation of freezing induced cell injury and extend the understanding on solution effects.

Animals↗

PubMed2004

Thermodynamic nonequilibrium phase change behavior and thermal properties of biological solutions for cryobiology applications.

Understanding the phase change behavior of biomaterials during freezing/thawing including their thermal properties at low temperatures is essential to design and improve cryobiology applications such as cryopreservation and cryosurgery. However, knowledge of phase change behavior and thermal properties of various biomaterials is still incomplete, especially at cryogenic temperatures (< or = -40 degrees C). Moreover, in these applications, chemicals are often added to improve their outcome, which can result in significant variation in the phase change behavior and thermal properties from those of the original biomaterials. These chemical additives include cryoprotective agents (CPAs), antifreeze protein (AFP), or cryosurgical adjuvants like sodium chloride (NaCl). In the present study, phase change behavior and thermal properties of saline solutions--either water-NaCl or phosphate buffered saline (PBS)--with various chemical additives were investigated. The chemical additives studied are glycerol and raffinose as CPAs, an AFP (Type III, molecular weight = 6500), and NaCl as a cryosurgical adjuvant. The phase change behavior was investigated using a differential scanning calorimeter (DSC) and a cryomicroscope. The specific and latent heat of these solutions were also measured with the DSC. The saline solutions have two distinct phase changes--water/ice and eutectic phase changes. During freezing, eutectic solidification of both water-NaCl and PBS are significantly supercooled below their thermodynamic equilibrium eutectic temperatures. However, their melting temperatures are close to thermodynamic equilibrium during thawing. These eutectic phase changes disappear when even a small amount (0.1 M glycerol) of CPA was added, but they are still observed after the addition of an AFP. The specific heats of these solutions are close to that of ice at very low temperatures (< or = -100 degrees C) regardless of the additives, but they increase between -100 degrees C and -30 degrees C with the addition of CPAs. The amount of latent heat, which is evaluated with sample weight, generally decreases with the addition of the additives, but can be normalized to approximately 300 J/g based on the weight of water which participates in the phase change. This illustrates that thermal properties, especially latent heat, of a biomaterial should be evaluated based on the understanding of its phase change behavior. The results of the present study are discussed in the context of the implications for cryobiology applications.

Biomimetic Materials↗

PubMed2004

Improved cryosurgery by use of thermophysical and inflammatory adjuvants.

In the present article, recent research efforts in our laboratory to improve cryosurgery by use of mechanistically derived adjuvants are reviewed. Our research has been focused on enhancing two freezing induced injury mechanisms - i) direct cell injury by use of thermophysical adjuvants, and ii) vascular injury by use of an inflammatory adjuvant. The thermophysical adjuvants are chemicals, usually salts, which can induce secondary crystallization, called eutectic solidification, in a cryolesion; thereby enhancing direct cell injury. The inflammatory adjuvant is a cytokine, tumor necrosis factor-alpha (TNF-alpha), which upregulates inflammation of microvasculature in tumors prior to freezing to promote vascular injury in the cryolesion. Even though the individual mechanism of injury enhancement within the cryolesion of each adjuvant requires further study, both adjuvants are envisioned to enlarge the complete killing zone so that the boundary of the cryolesion matches more closely with the edge of iceball. By bringing the edge of the cryolesion closer to the edge of iceball, the adjuvants hold promise for improvement of image guidance and outcome of cryosurgery.

Adjuvants, Immunologic↗