The scope of stem cell-based regenerative medicine is defined by the convergent repair triad of replacement, regeneration, and rejuvenation. The R3 paradigm of therapeutic repair highlights that these strategies overlap in practice while inherent distinctions conceptualize the scope of regenerative medicine, ranging from transplantation of used parts ( replacement ) to development of new parts ( regeneration ) to induction of self-renewed parts ( rejuvenation ).
The scope of regenerative medicine
Replacement
Replacement strategy refers to transplantation of a cell-based product that re-establishes homeostasis for the recipient through continuation of the tissue function from the donor. The field of surgery pioneered the concept of replacement with the advent of solid organ transplantation. If the heart was damaged beyond the ability to palliate the condition, then replacing the diseased tissue with a functioning donor heart became the only option. In addition to solid organ transplantation, cell-based replacement is routinely used in the form of red blood cell transfusions to replace the circulating blood in order to increase the oxygen-carrying capacity and treat life-threatening blood loss or anemia. This strategy recycles used parts of cells, tissues, or organs to restore physiologic function. A significant limitation of the replacement strategy remains the shortage of appropriate donors and the difficulty to match the immunological criteria for a safe and effective transplantation.
Regeneration
Regenerative strategy refers to engraftment of progenitor cells that require in vivo growth and differentiation to establish recipient homeostasis through de novo function of the stem cell-based transplant. Advances in hematology gave rise to the concept of regeneration with the identification of bone marrow-derived stem cells that once harvested could be transplanted in small quantities into the peripheral blood to engraft and reconstitute the functioning bone marrow through continuous production of the entire hematopoietic system. Success was facilitated by the presence of host bone marrow that provided a protective environment to nurture the long-term survival of self-renewing stem cell progenitors. This strategy restores function by renewing the pool of functional progenitor cells to allow differentiation as needed from exogenous stem cells. An intense search is ongoing for tissue-specific, nonhematopoietic stem cells that have the capacity to re-establish lost function when ectopically transplanted into a wide range of diseased tissues, as evident in diabetes, ischemic heart disease, and degenerative neurological diseases.
Rejuvenation
Rejuvenation strategy refers to self-renewal of tissues from endogenous, resident stem cells to maintain tissue homeostasis and promote tissue healing. This natural process of tissue recycling enables cells as they senesce to be replaced with younger cells that are inherently more resilient and equipped to provide adequate stress tolerance for tissue survival. Daughter cells can also be derived from reactivation of the cell cycle within mature cell types in response to (physio)pathological stress. This strategy renews tissue structure by recycling endogenous stem cells for proactive self-renewal. Rejuvenation ensures continuous production of renewable tissue required for long-term stress tolerance; however, most tissues are able to only partially self-renew. In the context of a massive acute injury, such as myocardial infarction, an inherent repair strategy may be inadequate. A boost in these natural processes, through biologic or pharmacologic treatment, is likely required to stimulate adaptive response and promote adequate biogenesis of functional tissue in the setting of acute or progressive disease.
