San Raffaele Telethon Institute for Gene Therapy

Senescence in stem cell aging, differentiation and cancer


Group Leader

Raffaella Di Micco



The group research activity is focused on dissecting the mechanisms that regulate cellular senescence during aging, differentiation and cancer. By combining cell and molecular biology approaches, together with quantitative imaging and next generation sequencing and clinically relevant human samples, the group is elucidating the functional role of senescence-associated pathways and regulators in the human hematopoietic stem cell compartment.

Research activity

The research of our group revolves around three main areas:

  1. Identification and targeting of senescence programs in hematopoietic stem and progenitor cell (HSPC)-based gene and cell therapies. HSPC exposure to currently available gene engineering approaches may inadvertently trigger the activation of a cellular senescence program, which may hamper the proliferation of gene-modified cells, affect their clonal composition and the dynamics of hematopoietic reconstitution upon transplantation. Our objectives are i) to elucidate the molecular determinants promoting senescence in HSPCs during ex-vivo manipulation and ii) to mitigate senescence barriers and to design innovative strategies for more effective, broader and safer gene therapy approaches.
  2. Deciphering molecular mechanisms of HSPC aging. The molecular mechanisms that regulate HSPC aging are thought to be cell-intrinsic, however, recent insights support the role for extrinsic factors produced locally by the niche in driving the aged phenotype. We aim to dissect the molecular factors contributing to the aged human hematopoietic compartment and to intervene to ameliorate age-associated HSPC dysfunctions.
  3. Senescence and epigenetic rewiring in leukemia response to therapy. Emerging evidence indicates that in response to a variety of anti-cancer treatments tumors engage cellular programs (e.g. senescence) that suppress neoplastic cells proliferation and promote many hallmarks of cancer. Our aim is to study how genetic alterations i) impact on hematological neoplasms, ii) alter treatment response, iii) contribute to tumor relapse and iv) create molecular vulnerabilities that may be targeted therapeutically.