Stem Cells

Developmental plasticity is a hallmark of stem cells, which are responsible for generating the distinctive cell types that form tissues and for replacing damaged cells. ^[1] Hematopoietic stem cells ensure a balanced production of all blood cells throughout life through self-renewal, differentiation, and migration controlled by their bone-marrow niche. ^{[2] [3]} Mesenchymal stem cells can be sourced from bone marrow, umbilical cord, adipose tissue, and placenta, and cells from different sources share similar characteristics with subtle differences. ^[4]

In transplantation, hematopoietic stem cells recruited from bone marrow to peripheral blood provide rapid and durable engraftment and reconstitution of functional bone marrow. ^[5] For mesenchymal stem cells the main regenerative mechanism is the secretome, the paracrine factors and extracellular vesicles they secrete, rather than direct differentiation into new tissue. ^[6] These paracrine factors act by regulating neuroprotective, anti-inflammatory, antiapoptotic, and angiogenic processes to promote tissue repair. ^[7]

A meta-analysis of 8 randomized trials (502 patients) found intra-articular mesenchymal stem cell injection significantly improved pain and function in unoperated knee osteoarthritis without a significant increase in adverse events. ^[8] A meta-analysis of 13 studies found mesenchymal stem cell transplantation lowered HbA1c and insulin requirements in diabetes without apparent adverse effects, positioning it as a possible treatment. ^[9] A meta-analysis of 42 randomized trials (2,183 participants) found mesenchymal stromal cell transplantation improved several autoimmune and rheumatic diseases and was relatively safe, while highlighting where further research is warranted. ^[10] For neurogenic bladder, although trials suggest safety, a meta-analysis found no significant functional improvement and noted the difficulty of interpretation given the lack of placebo controls. ^[11] In Crohn's disease, stem cell therapy seems potentially effective as an alternative for refractory disease, but toxicity remains the most significant barrier to systemic use. ^[12]

Stem cell exhaustion is one of the recognized biological hallmarks of aging, as somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. ^{[13] [14]} This makes rejuvenation of aged stem cells and their niches a promising target for therapeutic strategies aimed at extending tissue health span. ^[15] Cell-free approaches using the mesenchymal stem cell secretome are being explored for skin regeneration and rejuvenation, though standardized procedures are still needed for clinical translation. ^{[16] [6]}