History of stem cells: the discoveries that changed the field.

Discovery: McCulloch and Till provide classic experimental evidence that hematopoietic (blood-forming) stem cells exist in the bone marrow.

Impact: they establish an experimental basis for the modern idea of stem cells in adult tissues.

Limitation: the context is still confined to hematopoietic biology, not to pluripotency in general.

Discovery: John B. Gurdon shows that the nucleus of a differentiated cell can be reprogrammed.

Impact: it opens up the conceptual framework that will make cell reprogramming plausible decades later.

Limitation: this is not yet a clinical technology, nor are these modern iPS cells.

Discovery: the first successful allogeneic transplants of hematopoietic cells, mainly in severe immunodeficiencies.

Impact: the field enters modern clinical medicine and shows that cell transplantation can become a life-saving treatment.

Limitation: very specific indications and high procedural complexity; toxicity and compatibility remain central issues.

Discovery: isolation of mouse embryonic stem cells by Evans and Kaufman.

Impact: it changes developmental biology and makes it possible to study pluripotency experimentally in the laboratory.

Limitation: this is a mouse system, not yet human pluripotent cells.

Discovery: isolation of mouse and human hematopoietic stem cells, with a better experimental definition of HSCs.

Impact: it strengthens the bridge between biological definition, transplantation and the development of more refined protocols.

Limitation: characterization remains confined to the hematopoietic compartment.

Discovery/recognition: Nobel Prize to E. Donnall Thomas for his contribution to the development of hematopoietic transplantation.

Impact: it confirms the value of hematopoietic cell transplantation as a major chapter of modern medicine.

Limitation: the recognition concerns a specific field, not all stem cell applications.

Discovery: James Thomson and colleagues describe human embryonic stem cell lines derived from blastocysts.

Impact: it opens a new phase of research on human pluripotent cells and on controlled differentiation.

Limitation: ethical issues and problems of clinical translation are central from the outset.

Discovery: Takahashi and Yamanaka report the generation of iPS cells from mouse fibroblasts using defined factors.

Impact: it changes the field of cell reprogramming and redraws the relationship between adult cells and pluripotency.

Limitation: it is still a mouse system, and the biological safety of reprogramming remains an open question.

Discovery: human iPS cells arrive: the work of Takahashi and colleagues extends reprogramming to adult human fibroblasts.

Impact: the technology becomes central to disease models, pharmacology and the biology of human pluripotency.

Limitation: challenges remain regarding genomic stability, quality and clinical transferability.

Discovery: organoids from a single Lgr5+ stem cell: the work of Sato and Clevers shows that single intestinal cells can build crypt-villus structures in vitro.

Impact: it accelerates disease modeling, tissue physiology and experimental testing on organoids.

Limitation: an organoid is not a complete organ and is not the same as a clinical therapy.

Discovery/recognition: Nobel Prize to Gurdon and Yamanaka for showing that mature cells can be reprogrammed to a pluripotent state.

Impact: it consolidates reprogramming as a major biological paradigm of the field.

Limitation: scientific recognition does not remove the barriers to safe and standardized clinical applications.

Discovery/approval: Holoclar becomes the first stem cell-based product recommended/approved in the EU for a specific ophthalmological indication.

Impact: it marks an important step in the regulated clinical translation of advanced cell therapies.

Limitation: this is a very specific indication and product, not a general validation of the field.

Regulatory event: regulatory agencies keep stressing the problem of unapproved products: the FDA and other bodies step up public communication against unvalidated regenerative medicine offerings.

Impact: they make it clear to patients and clinicians that many market offerings do not correspond to approved or adequately tested treatments.

Limitation: regulatory communication alone does not solve the problem of aggressive marketing or medical tourism.

Approval: Ryoncil is approved by the FDA as the first mesenchymal stromal cell therapy for steroid-refractory acute GVHD in pediatric patients.

Impact: it shows that the field keeps advancing, but for extremely specific indications and under strict regulation.

Limitation: it does not justify generalizations about the value of all commercial mesenchymal or regenerative therapies.

Approval: the EU grants a conditional marketing authorization to Zemcelpro (dorocubicel), cord blood stem cells partly multiplied in the laboratory, for adults with blood cancers who need an allogeneic transplant and have no other suitable donor cells available.

Impact: it widens the options for hematopoietic transplantation for people who cannot find a compatible donor.

Limitation: conditional marketing authorization, granted on less complete data than usual to address an unmet medical need; narrow indication.

Approval: the FDA (December 9, 2025) and then the EU (January 9, 2026) approve Waskyra (etuvetidigene autotemcel): in the laboratory, a working copy of the WAS gene is added to the patient's hematopoietic stem cells using a lentiviral vector. The authorization holder is Fondazione Telethon; the therapy is the result of decades of research at SR-Tiget in Milan.

Impact: it brings blood stem cell gene therapy to a rare inherited immunodeficiency; according to Telethon, it is the first ex vivo gene therapy brought from research to approval by a non-profit organization.

Limitation: narrow indication (mutation of the WAS gene, transplant appropriate but no suitable HLA-matched donor); it is gene addition, not genome editing like Casgevy.

Approval: on March 6, 2026, Japan's Ministry of Health, Labour and Welfare authorizes the world's first two products derived from iPS cells: AMCHEPRY (raguneprocel), allogeneic dopaminergic neural progenitors for the motor symptoms of Parkinson's disease that do not respond adequately to medication, including levodopa; and RiHEART, sheets of allogeneic cardiomyocytes applied to the surface of the heart in severe ischemic heart failure.

Impact: twenty years after Takahashi and Yamanaka's first iPS cells (2006), cell reprogramming reaches products authorized for clinical use.

Limitation: conditional and time-limited approval, granted with safety confirmed and efficacy considered plausible: efficacy must be demonstrated within 7 years. It applies only in Japan and does not amount to routine use.