Inflammatory bowel disease
ESC-derived MSCs promoted colon epithelial integrity and regeneration by elevating circulating IGF-1 in colitis mice (Theranostics, 2020).
Research programmes
Where the biology is tested
Disease areas under active investigation, the models we use, and the published evidence behind each line of work.
Lead programme
Multiple sclerosis
Multiple sclerosis is a demyelinating disease of the central nervous system in which the insulating sheath of nerve fibres is lost, disrupting transmission between brain and body. It presents in relapsing–remitting, secondary progressive and primary progressive forms, and patients experience disability across movement, vision, sensation, cognition, ambulation and balance.
Roughly twenty disease-modifying agents are approved. None is curative; they aim to shorten relapses and slow the accrual of disability, and many carry substantial adverse effects — injection-site reactions, bradycardia, macular oedema, lymphopenia and opportunistic infection among them. The unmet need is real, and it is what our lead programme addresses.
What we found
In 2014, Dr Xiaofang Wang and colleagues reported in Stem Cell Reports that hESC-derived MSCs outperform bone marrow MSCs in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. hES-MSCs significantly attenuated disease scores relative to BM-MSCs from several donors, and the effect held whether cells were given prophylactically or therapeutically. hES-MSCs effectively prevented demyelination in treated animals.
The mechanistic reading is consistent with the cytokine data. Bone marrow MSCs express high levels of IL-6, a pro-inflammatory cytokine that can worsen autoimmune disease; hES-MSCs do not. In the brains of EAE animals, hES-MSC treatment was associated with reduced CD4+, CD8+, Th1 and Th17 T-cell infiltration compared with BM-MSC treatment, alongside markedly lower MHC class II expression on the administered cells themselves.
The finding was extended to a primate model in 2018: intrathecal delivery of hESC-derived MSC spheres promoted recovery in a non-human primate multiple sclerosis model (Cell Death Discovery, 4:28).
Open questions. How long do infused cells persist, and does persistence predict effect? How much of the benefit is cell-intrinsic versus mediated by secreted vesicles? Does route of delivery — intravenous versus intrathecal — change the mechanism rather than just the dose reaching the CNS?
Our own studies have begun to address these questions, in different animal models and by different routes. Wang X, et al. reported the in vivo fate of T-MSC spheroids applied topically to a skin wound (Theranostics, 2019, 9(21):6112–6128), and Yeung CK, et al. established how long intravenously injected T-MSC spheroids and dissociated T-MSCs persist in cynomolgus monkeys, where they distribute, and why (Biomaterials, 2022, 289:121759).
Rare disease
Cerebral adrenoleukodystrophy
Cerebral adrenoleukodystrophy is an X-linked recessive disease in which mutations in ABCD1 cause very long chain fatty acids to accumulate in brain and adrenal gland, demyelinating nerve fibres. Prevalence is roughly 1 in 100,000; about 95% of those affected are male. Early signs — behavioural change, poor memory, difficulty reading and writing — are non-specific, which makes early diagnosis hard. Untreated, cALD progresses rapidly, often to a vegetative state or death within two to five years.
Haematopoietic stem cell transplantation is the only effective intervention, and only when performed before neurological symptoms and extensive demyelination appear. Performed later it can accelerate decline. It further requires an HLA-matched donor and carries risks of graft-versus-host disease and prolonged immune deficiency. Gene therapy correcting the patient's own HSCs shows comparable efficacy in pilot studies, but neither approach restores adrenal function.
The research rationale for T-MSCs
- No donor matching. T-MSCs express much lower HLA levels than adult tissue-derived stem cells, so there is no requirement to find a matched donor and a lower expected burden of GvHD and immunosuppression.
- Barrier stabilisation. Our in vitro work indicates T-MSCs can cross the blood–brain barrier and reduce its permeability — a plausible route to suppressing neuroinflammation by limiting recruitment of activated T cells across the barrier.
- A tractable substrate for engineering. Because T-MSCs expand almost indefinitely while retaining normal cellular properties, they are a practical target for genetic modification.
This programme is pursued in collaboration with Dr Troy Lund at the University of Minnesota, who has studied one of the largest cohorts of cALD patients to have received HSCT.
Acute injury
Acute respiratory distress syndrome
ARDS is respiratory failure driven by acute inflammation in the lung following illness or injury. Damage to the alveolar–capillary barrier, surfactant depletion and loss of aerated tissue produce increased permeability and pulmonary oedema. More than three million people are affected annually. A multicentre study of over 29,000 patients across 50 countries found that ARDS criteria were met by 10% of ICU admissions and 23% of ventilated patients, with mortality of 40–50%. Sepsis and bacterial or viral pneumonia account for 40–60% of cases.
Pharmacological intervention has repeatedly failed in trials. Care remains supportive — mechanical ventilation, fluid management, oxygen supplementation, prone positioning, ECMO. Our interest follows from the platform's anti-inflammatory profile and from work on the alveolar barrier.
Wider preclinical work
Other indications under investigation
Additional areas the laboratory has researched, each with published output in the record.
Osteoarthritis
Transplantation of hESC-derived MSC spheroids ameliorated spontaneous osteoarthritis in rhesus macaques (Theranostics, 2019).
Wound healing
Noninvasive application of hESC-derived MSC spheres accelerated wound healing in a CXCL12–CXCR4 axis-dependent manner (Theranostics, 2019), with later work on spheroid delivery in diabetic wounds.
Radiation brain injury
MSCs attenuated radiation-induced brain injury by inhibiting microglial pyroptosis (BioMed Research International, 2017).
Dopaminergic injury
Exosome and small extracellular vesicle studies in Parkinson's disease models address Nox4/ROS/Nrf2 signalling and caspase-mediated apoptosis (2023, 2026).
Graft-versus-host disease
A comparative study of T-MSCs against bone marrow MSCs in acute xenogeneic GvHD in humanized mice (Transplantation, 2026).
Adipocyte transplantation
hESC-derived MSCs enhanced fat engraftment by promoting adipocyte reaggregation, secreting CCL2 and mobilising macrophages (Biomaterials, 2021).
Developmental potency
Blastocyst injection revealed contribution of hES-derived MSCs to skeletal, dermal and extraembryonic tissues, and partial rescue of skeletal defects in Sox9+/− fetuses (Cell Reports, 2023).
Further areas
Type 1 diabetes, neuromyelitis optica, arthritis, stroke and Parkinson's disease have all been investigated preclinically within the laboratory's wider programme.
Methods
Models and assays in routine use
| Model or assay | Question it answers |
|---|---|
| EAE (mouse) | Does treatment attenuate autoimmune demyelinating disease, prophylactically and therapeutically? |
| Primate MS model | Does the effect survive translation to a species closer to human, and how does delivery route matter? |
| DSS colitis (mouse) | Effects on epithelial integrity and regeneration in mucosal inflammation. |
| Spontaneous OA (rhesus macaque) | Efficacy in naturally occurring, non-induced degenerative joint disease. |
| Humanized-mouse xenogeneic GvHD | Immunomodulatory potency against a human T-cell-driven alloresponse. |
| In vitro blood–brain barrier | Effects on barrier permeability under TNF-α challenge. |
| Blastocyst injection / chimera | What are these cells developmentally, read out in a living embryo? |
| NK cytotoxicity assays | Susceptibility of infused cells to innate clearance, and whether it can be engineered away. |
| Cytokine and MHC profiling | Quantitative immunological comparison against adult tissue-derived MSCs. |
| GLP toxicology and biodistribution | Where cells go after infusion, and the safety profile required to support an IND. |