Epigenetic modulation inhibits epithelial-mesenchymal transition-driven fibrogenesis and enhances characteristics of chemically-derived hepatic progenitors

Michael Adisasmita,Hyomin K Lee,Yohan An,Myounghoi Kim,Michael Girma Mamo,Junho K. Hur,Dongho Choi,Ji Hyun Shin,Yun Kyung Jung 대한외과학회 2024 Annals of Surgical Treatment and Research(ASRT) Vol.106 No.5

Purpose: One of the novel cell sources of cell-based liver regenerative medicine is human chemically-derived hepatic progenitors (hCdHs). We previously established this cell by direct hepatocyte reprogramming with a combination of small molecules (hepatocyte growth factor, A83-01, CHIR99021). However, there have been several issues concerning the cell’s stability and maintenance, namely the occurrences of epithelial-mesenchymal transition (EMT) that develop fibrotic phenotypes, resulting in the loss of hepatic progenitor characteristics. These hepatic progenitor attributes are thought to be regulated by SOX9, a transcription factor essential for hepatic progenitor cells and cholangiocytes. Methods: To suppress the fibrotic phenotype and improve our long-term hCdHs culture technology, we utilized the epigenetic modulating drugs DNA methyltransferase inhibitor (5-azacytidine) and histone deacetylase inhibitor (sodium butyrate) that have been reported to suppress and revert hepatic fibrosis. To confirm the essential role of SOX9 to our cell, we used clustered regularly interspaced short palindromic repeats-interference (CRISPRi) to repress the SOX9 expression. Results: The treatment of only 5-azacytidine significantly reduces the fibrosis/mesenchymal marker and EMT-related transcription factor expression level in the early passages. Interestingly, this treatment also increased the hepatic progenitor markers expression, even during the reprogramming phase. Then, we confirmed the essential role of SOX9 by repressing the SOX9 expression with CRISPRi which resulted in the downregulation of several essential hepatic progenitor cell markers. Conclusion: These results highlight the capacity of 5-azacytidine to inhibit EMT-driven hepatic fibrosis and the significance of SOX9 on hepatic progenitor cell stemness properties.

Kangaroo mother care practices for low birthweight newborns in a district hospital in Indonesia

Choirunisa, Septyana,Adisasmita, Asri,Izati, Yulia Nur,Pratomo, Hadi,Iriani, Dewi Korean Academy of Child Health Nursing 2021 Child Health Nursing Research Vol.27 No.4

Purpose: Kangaroo mother care (KMC) was introduced in Indonesia 30 years ago, but the extent of its use has not been fully documented. Therefore, this study aimed to examine the use of KMC and evaluate the characteristics of infants who received KMC at Koja District Hospital in North Jakarta, Indonesia. This retrospective cohort study recorded the characteristics of infants with birthweights less than or equal to 2,200 g at the above-mentioned hospital. Methods: Data collected from infant registers included gestational age, birthweight, Apgar score, number of complications, history of neonatal intensive care unit treatment, and KMC status. Cox regression analysis was conducted. Results: This study found that 57.7% of infants received KMC. Infants with birthweights over 1,500 g were 2.16 times (95% CI: 1.20-3.89) more likely to receive KMC. Conclusion: Efforts to promote KMC are recommended, specifically for infants with birthweights greater than 1,500 g. KMC for infants with other conditions can also be considered based on the infants' stability.

Knowledge and perceptions of kangaroo mother care among health providers: a qualitative study

Pratomo, Hadi,Amelia, Tiara,Nurlin, Fatmawati,Adisasmita, Asri C. The Korean Pediatric Society 2020 Clinical and Experimental Pediatrics (CEP) Vol.63 No.11

Background: Indonesia is one of the countries with the highest preterm birth rate. Preterm infants are more likely than term and normal weight infants to experience neonatal mortality and morbidity due to acute respiratory, gastrointestinal, immunologic, central nervous system, hearing, and vision problems. Kangaroo mother care (KMC) is a proven cost-effective intervention to help reduce mortality rates among preterm infants; however, it has not been fully implemented in hospitals. Purpose: Assess KMC knowledge and perceptions among health providers. Methods: This qualitative study was conducted from December 2015 to April 2016 and consisted of 21 in-depth interviews and 3 focus group discussions (FGDs). The 3 categories of health personnel in the study were clinical providers, hospital management representatives, and Indonesian Midwife Association members. Results: Most health providers know about the benefits of KMC including stabilizing temperatures, weight gain, and maternal-infant bonding and reducing human resources and labor costs. They were also aware of which newborns were eligible for KMC treatment. Their knowledge was mostly gained from observation or obtained from pediatricians and personal experience. They believed that a low birth weight infant in an incubator could not be treated with KMC and that it could only be practiced if a special gown was used when holding the baby. This perception could be caused by a lack of formal KMC training, leading to misunderstanding of its aspects. Conclusion: In conclusion, KMC knowledge of clinical providers in the 2 hospitals was sufficient, primarily due to their health-related educational background. Some perceptions could be potential barriers to or facilitate the implementation of KMC practice. These perceptions should be considered in future KMC training designs.

Effect of premature rupture of membranes on preterm labor: a case-control study in Cilegon, Indonesia

Ita Marlita Sari,Asri C,Adisasmita,Sabarinah Prasetyo,Dwirani Amelia,Ratih Purnamasari 한국역학회 2020 Epidemiology and Health Vol.42 No.-

OBJECTIVES: The global prevalence of preterm labor is approximately 11.1% of live births. However, preterm labor contributes to 75-80% of neonatal morbidity and mortality. The morbidity experienced by preterm infants may continue to influence their subsequent development, imposing physical, psychological, and economic burdens. Premature rupture of membranes (PROM) is a causal factor that may affect preterm birth. Previous studies have shown an association between PROM and preterm labor, but this association should be investigated in more diverse populations. Therefore, this study was conducted in Cilegon, Indonesia to determine the magnitude of the risk of preterm labor associated with PROM at Cilegon Hospital from July 2014 to December 2015. METHODS: This case-control study used data from patients’ medical records. The cases were all mothers who delivered at less than 37 weeks of gestation, while the control population comprised all mothers who delivered at greater or equal to 37 weeks. The data were analyzed using logistic regression. RESULTS: The bivariate analysis yielded an odds ratio (OR) of 2.97 (95% confidence interval [CI], 1.92 to 4.59) before controlling for covariates. The model derived through multiple regression analysis after controlling for education, history of preterm labor, and anemia resulted in an OR of 2.58 (95% CI, 1.68 to 3.98). CONCLUSIONS: Mothers who experience PROM during pregnancy were at a 2.58 times higher risk of preterm labor after controlling for education, history of preterm labor, and anemia.

Enhancing generation efficiency of liver organoids in a collagen scaffold using human chemically derived hepatic progenitors

Myounghoi Kim,Yohan Kim,Elsy Soraya Salas Silva,Michael Adisasmita,Kyeong Sik Kim,Yun Kyung Jung,Kyeong Geun Lee,Ji Hyun Shin,Dongho Choi 한국간담췌외과학회 2023 Annals of hepato-biliary-pancreatic surgery Vol.27 No.4

Backgrounds/Aims: Liver organoids have emerged as a powerful tool for studying liver biology and disease and for developing new therapies and regenerative medicine approaches. For organoid culture, Matrigel, a type of extracellular matrix, is the most commonly used material. However, Matrigel cannot be used for clinical applications due to the presence of unknown proteins that can cause immune rejection, batch-to-batch variability, and angiogenesis. Methods: To obtain human primary hepatocytes (hPHs), we performed 2 steps collagenase liver perfusion protocol. We treated three small molecules cocktails (A83-01, CHIR99021, and HGF) for reprogramming the hPHs into human chemically derived hepatic progenitors (hCdHs) and used hCdHs to generate liver organoids. Results: In this study, we report the generation of liver organoids in a collagen scaffold using hCdHs. In comparison with adult liver (or primary hepatocyte)-derived organoids with collagen scaffold (hALO_C), hCdH-derived organoids in a collagen scaffold (hCdHO_C) showed a 10-fold increase in organoid generation efficiency with higher expression of liver- or liver progenitor-specific markers. Moreover, we demonstrated that hCdHO_C could differentiate into hepatic organoids (hCdHO_C_DM), indicating the potential of these organoids as a platform for drug screening. Conclusions: Overall, our study highlights the potential of hCdHO_C as a tool for liver research and presents a new approach for generating liver organoids using hCdHs with a collagen scaffold.