Stem cell platforms for regenerative medicine

Abstract

The pandemic of chronic degenerative diseases associated with aging demographics mandates development of effective approaches for tissue repair. As diverse stem cells directly contribute to innate healing, the capacity for de novo tissue reconstruction harbors a promising role for regenerative medicine. Indeed, a spectrum of natural stem cell sources ranging from embryonic to adult progenitors has been recently identified with unique characteristics for regeneration. The accessibility and applicability of the regenerative armamentarium has been further expanded with stem cells engineered by nuclear reprogramming. Through strategies of replacement to implant functional tissues, regeneration to transplant progenitor cells or rejuvenation to activate endogenous self-repair mechanisms, the overarching goal of regenerative medicine is to translate stem cell platforms into practice and achieve cures for diseases limited to palliative interventions. Harnessing the full potential of each platform will optimize matching stem cell-based biologics with the disease-specific niche environment of individual patients to maximize the quality of long-term management, while minimizing the needs for adjunctive therapy. Emerging discovery science with feedback from clinical translation is therefore poised to transform medicine offering safe and effective stem cell biotherapeutics to enable personalized solutions for incurable diseases.

Keywords: adult; allogeneic; autologous; bioengineered; embryonic; immune response; perinatal.

Figure 1

Embryonic stem cells. Isolated from the inner cell mass (ICM) of a blastocyst, embryonic stem cells are cultured to produce cell lines that can be indefinitely propagated in the undifferentiated state. Consistent with the characteristic ability to recapitulate normal embryonic development, embryonic stem cells differentiate in vitro to produce tissues arising from all three germinal layers. The ectoderm develops into neuronal derivatives within the central nervous system. The mesoderm produces mature tissues, such as heart muscle. The endoderm differentiates into lineages such as pancreas. The pluripotency and unlimited proliferation makes embryonic stem cells an attractive source for regenerative medicine applications.

Figure 2

Perinatal stem cells. Umbilical cord blood is one source of perinatal stem cells collected at birth from the umbilical vein containing blood returning from the placenta. These cells have been utilized as hematopoietic stem cells similar to adult bone marrow‐derived progenitors. The immaturity of the immune system reduces the risk of detrimental graft‐versus‐host disease when comparing perinatal to adult sources. Perinatal stem cells also contain populations of cells that behave similar to embryonic stem cells. Pluripotent differentiation potential and unique immunologic status highlight the advantages of perinatal stem cells for regenerative applications, and justify a distinct classification. Perinatal stem cells that also include amniotic epithelial cells (AECs) offer readily available, alternative sources of progenitors.

Figure 3

Adult stem cells. Derived from nonembryonic or nonperinatal sources, adult stem cells can be procured from a range of tissues, such as bone marrow, as well as circulating blood or fat. Adult stem cells are generally considered multipotent, as illustrated for bone marrow‐derived stem cells that contain both hematopoietic progenitors and mesenchymal stem cells. Hematopoietic stem cells give rise to (i) lymphoid‐derived T cells, B cells, and natural killer cells; and (ii) myeloid‐derived red blood cells, platelets, and macrophages. Hematopoietic stem cells provide the standard of care for bone marrow reconstitution. Mesenchymal stem cells also have a diverse spectrum of differentiation that includes bone, muscle, cartilage, cardiomyocyte, hepatocyte, and neurons. Mesenchymal stem cells serve as a cell type of choice for clinical applications of nonhematological regeneration based on the availability of autologous stem cell sources, cost‐effective isolation, and safety profi le.

Figure 4

Bioengineered stem cells. Pluripotent stem cells that function like embryonic stem cells can be engineered from adult somatic cells through “therapeutic cloning” or “nuclear reprogramming.” Therapeutic cloning combines the nuclear content of a somatic cell obtained from an adult biopsy with cytoplasmic/plasmalemma components from an enucleated donor oocyte. Transfer of the somatic cell nucleus into the remnant of the fertilized egg is performed by micromanipulation. This process results in cloned cells, instructed by the oocyte cytoplasm, that develop into a blastocyst allowing harvest of embryonic stem cells from the inner cell mass (ICM). Alternatively, nuclear reprogramming of fibroblast cells from adults can be achieved through transient ectopic expression of four genes (OCT4 and SOX2 with either NANOG and LIN28 or KLF4 and c‐Myc) to produce pluripotent cells with embryonic stem cell features, called induced pluripotent stem (iPS) cells. The resulting bioengineered stem cells obtained from both approaches are bona fide pluripotent cells demonstrated by their ability to independently produce an entire organism from embryonic to adult stages of development. Importantly, the tissues derived from these engineered stem cells are genetically similar to the original somatic cell biopsy. This technology produces autologous, embryonic‐like stem cells that may enable individualized cell‐based therapy.