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Regenerative medicine encompasses all therapeutic approaches to enhance repair processes by replacing or regenerating cells, tissues, or organs to restore health. At its core, outcomes in regenerative medicine are influenced by the genome, the patient, and the cell (Fig. 95–1). Although diverse strategies have been examined, (e.g., stem cells from diverse sources, biomaterials, tissue engineering products, and neo-organogenesis), regenerative medicine is driven by the capacity of stem cells to acquire multiple and discrete fates, a property that can be exploited to repair and/or replace damaged tissue for improved therapeutic and functional outcome.

Figure 95–1

Factors of regenerative medicine: The three-body problem of regenerative medicine. The three factors—cell, genome, and patient—influence each other in complex and sometimes unexpected ways. These three separate scientific foci of regenerative medicine must be developed in the context of one another to have meaningful impact. (Reproduced with permission from Tolar J, Osborn M, Daughters R, Banga A, Wagner J. Regenerative Medicine: Multipotential Cell Therapy for Tissue Repair. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri M, eds. Williams Hematology, 9e New York, NY: McGraw-Hill;2016.)

The discovery of cells that exhibited self-renewal and potency was the first identification of a new type of cells: embryonic stem cells.1 However, the earliest conceptual understanding of the “epigenetic landscape” that is the basis for current understanding of stem cell plasticity was suggested in 1957 by CH Waddington.2 Conceptually, Waddington likened embryonic stem cells to a marble sitting at the top of a hill poised to roll down and end up in any number of valleys. From this, it was understood that multiple paths could be taken by an embryonic stem cell to acquire its final phenotype. Although some tissues retain a pool of resident, semi-differentiated stem cells for limited repair and renewal, once an embryonic stem cell is committed to a specific cellular fate, it is considered terminally differentiated and the energy required to push it back up the hill to effect a “reset” is insurmountable (Fig. 95–2).

Figure 95–2

Classic model of differentiation: Development of various formed elements of the blood from bone marrow cells. Cells below the horizontal line are found in normal peripheral blood. The principal sites of action of erythropoietin (erythro) and the various colony-stimulating factors (CSF) that stimulate the differentiation of the components are indicated. Erythro, erythropoietin; G, granulocyte; IL, interleukin; M, macrophage; SCF, stem cell factor; thrombo, thrombopoietin. (Reproduced with permission from Blood as a Circulatory Fluid & the Dynamics of Blood & Lymph Flow. In: Barrett KE, Barman SM, Boitano S, Brooks HL, eds. Ganong's Review of Medical Physiology, 25e New York, NY: McGraw-Hill;2017.)

This initial framework to explain the concept of pluripotency was dramatically ...

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