The Human Cell Atlas (HCA) marks a decade of transforming how we understand human biology, with profound implications for regenerative medicine. In a recent thought leadership webinar, we interviewed Professor Fiona Watt of EMBL, who reflected on the journey of the HCA and its impact on tissue biology, disease research, and translational science. The session, followed by a panel discussion moderated by Professor Watt, brought together leading experts Professor Maria Kasper (Karolinska Institutet) and Professor Karl Koehler (Harvard Medical School and Boston Children’s Hospital) to explore advances in spatial proteomics, single-cell transcriptomics, clinical translation, and the collaborative infrastructure shaping the future of tissue biology.
Balancing Stem Cells and Differentiation
Professor Watt’s career has centred on a fundamental biological principle: tissue health depends on balance. Rather than viewing stem cells as inherently “good” and differentiated cells as “bad,” her work emphasizes homeostasis — the dynamic equilibrium between cell renewal and specialization.
In wound repair, this balance temporarily shifts toward stem cell expansion before restoring normal tissue structure. In inflammatory diseases such as psoriasis, targeted biologic therapies can reestablish equilibrium. Cancer, however, represents a more complex breakdown of this balance. In squamous cell carcinomas, tumor grading reflects the proportion of differentiated cells — the closer the tumor resembles normal tissue, the better the prognosis tends to be.
These insights have shaped regenerative medicine’s understanding that successful therapies must restore balance, not simply increase stem cell numbers.
From Single Cells to Global Infrastructure
Professor Watt was present at the launch of the Human Cell Atlas a decade ago, recognizing early the promise of single-cell RNA sequencing. What began as technically limited single-cell experiments has evolved into a global scientific infrastructure.
Today, the HCA comprises 18 biological networks and nearly 200 published studies, shifting from static cell catalogues toward connected, semi-global references spanning development, immunity, and barrier tissues such as skin.
Importantly, the field has moved beyond asking “What cell types exist?” to “How do cell states function, interact, and change?”
Skin Biology: Diversity in Context
Through her lab’s contributions to comprehensive skin atlases across development, adulthood, and inflammatory disease, Professor Watt highlighted a key insight: most tissues do not harbour entirely new cell types across anatomical sites — instead, cell abundance and state vary.
Furthermore, in basal cell carcinoma, cancer-associated fibroblasts were shown to represent expansion of pre-existing populations rather than novel cell types. Meanwhile, immune cell diversity across tissues has emerged as central to understanding both regeneration and pathology.
Yet single-cell data also raise new questions. While transcriptional heterogeneity is well established, interpreting its functional meaning remains one of the field’s biggest challenges.
Advances in Spatial Proteomics and Transcriptomics
The panel discussion emphasized how spatial technologies are redefining tissue analysis.
Spatial transcriptomics and multiplexed in situ approaches overcome biases introduced by tissue dissociation, revealing cell populations that may otherwise be underrepresented. New spatial omics platforms allow researchers to interrogate the expression of thousands of genes or over 100 proteins within a single tissue section, integrating cell identity with anatomical context.
These advances are transforming the Human Cell Atlas from a list of cell types into a functional tissue map.
Organoids and Regenerative Applications
Professor Karl Koehler — Associate Professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and Principal Investigator at Boston Children’s Hospital — discussed how organoid systems are being guided by HCA reference data.
Complex skin and inner ear organoids derived from pluripotent stem cells now model development and disease with increasing fidelity. While clinical translation remains challenging, stem-cell derived therapies for diabetes and Parkinson’s disease signal that regenerative medicine is entering a new phase.
Organoid systems also provide platforms for gene therapy testing in congenital disorders such as epidermolysis bullosa and Usher syndrome.
Data Integration: The Persistent Bottleneck
Despite extraordinary progress, data integration remains difficult.
Professor Maria Kasper — Associate Professor of Cell and Molecular Biology at Karolinska Institutet — noted challenges in harmonizing metadata, regulatory barriers to raw data sharing across countries, and inconsistent annotation practices in earlier studies.
The HCA is working toward structured data portals and shared nomenclature frameworks, while building a “living reference atlas” that evolves with new data requires both technical and cultural shifts.
The question moving forward is whether the Atlas should remain a static reference or become a dynamic, continuously updated biological model.
Challenges in Clinical Development
Bringing single-cell and spatial technologies into clinical practice demands regulatory rigor, validation standards, and scalable workflows.
One promising direction involves applying AI to archived pathology slides, enabling insights from HCA research to inform decades-old tissue samples. If successful, this could bridge discovery science and routine diagnostics.
However, as panelists emphasized, translating regenerative approaches — particularly complex organoid-based therapies — requires sustained investment and long-term commitment.
Leadership and Scientific Equity
Beyond laboratory science, Professor Watt’s leadership roles — including former Executive Chair of the UK Medical Research Council and current EMBO Director — reflect her commitment to strengthening research ecosystems.
From supporting clinician-scientists to promoting equitable opportunities across Europe, she underscored that scientific excellence can emerge anywhere and can be nurtured given the right colleagues, infrastructure and collaborations.
Looking Ahead
The next decade of regenerative medicine will require integrating cell type, spatial location, and functional behaviour into cohesive models of tissue biology.
If the first ten years of the Human Cell Atlas were about mapping, the next ten will be about application — translating cellular insight into therapies that restore balance, repair tissues, and improve human health.
