Research

Research 1. Optimization of dopaminergic progenitor and neuron differentiation

Current dopaminergic cell differentiation yields a mixed population consisting of approximately 80-90% dopaminergic progenitor cells and 10-20% TH+ dopaminergic neurons. Depending on the transplantation microenvironment and therapeutic strategy, progenitor cells and mature neurons exhibit distinct biological properties and therapeutic advantages. Therefore, achieving a pure population of dopaminergic progenitors and neurons is critical for maximizing therapeutic efficacy. Our lab is developing precise differentiation protocols targeting cell fate determination pathways by modulating extracellular signaling, transcription factor combinations, and culture conditions to achieve 100% dopaminergic neuron yield. This approach is expected to enhance the consistency and reproducibility of cell-based therapies, improving post-transplantation survival and functional integration. 

Research 2. Optimization of cryopreservation and storage of dopaminergic neurons

Dopaminergic neurons are highly vulnerable to cold-induced stress due to their distinct lipid membrane composition, mitochondrial activity, and cytoskeletal structure. Conventional cryopreservation buffers and storage methods frequently result in cell death and functional decline. To address these challenges, our lab is developing a novel cryopreservation buffer designed to enhance cell survival by regulating intracellular osmotic balance, inhibiting reactive oxygen species (ROS), and etc. This approach aims to minimize cellular damage during the freeze-thaw process and maintain the structural and functional integrity of dopaminergic neurons prior to transplantation. 

The transplantation of stem cell-based therapeutics often triggers a robust inflammatory response within the brain due to needle-induced tissue damage (Needle Trauma). This inflammatory microenvironment significantly compromises the survival, engraftment, and functional integratioin of transplanted stem cells. To mitigate this challenge, our lab recently developed and reported a co-transplantation strategy involving the direct delivery of regulatory T cells (TREG) into the brain. TREG play a crucial role in modulating local immune responses by suppressing pro-inflammatory cytokine release and enhancing immune tolerance, thereby promoting the survival and functional integration of transplanted stem cells. 

In addition to TREG-based strategies, we are actively investigating alternative approaches to further enhance therapeutic efficacy. These influde:

Cell Encapsulation: Encasing stem cells within biocompatible hydrogel or polymer-based scaffolds to provide a protective barrier against immune attack and inflammatory stress while maintaining neutrient and oxygen exchange.

Antibody-based Therapies: Targeting specific inflammatory cytokines (e.g., TNF, IL1) and immune cell receptors to reduce the inflammatory cascade and protect transplanted cells.

Small molecule compounds: Developing small molecule inhibitors of inflammatory signaling pathways (e.g., NFkB, JAK/STAT) to downregulate inflammatory responses and support cell survival.

This multi-faceted approach aims to establish an optimal transplantation microenvironment, thereby improving cell survival rates, enhancing functional integration, and ultimately maximizing the clinical efficacy of stem cell-based regenerative therapies.