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CHAPTER 30 INTRODUCTION

REGENERATIVE Regenerative medicine is a concept that evolved from knowledge in
genome regulation and modification, from understanding of embryonic
MEDICINE: MULTIPOTENTIAL development and “stemness” of cells, and from 50 years of experience
in human transplant biology. Therefore, a narrow view of any of these
disciplines is not sufficient for illuminating the mechanisms of action
CELL THERAPY FOR TISSUE underlying the already accomplished successes and for guiding the
potential of novel basic biology discoveries into clinically meaningful
REPAIR regenerative medicine (Fig. 30–1).
Accordingly, this chapter spans major organ systems (marrow,
liver, pancreas, brain, and spinal cord) to demonstrate their connec-
tivity and shared biologic responses deployed at the times of acute and
Jakub Tolar, Mark J Osborn, Randy Daughters, Anannya Banga, and chronic injury. Furthermore, the goals of regenerative therapies are
different than those of commonly used drugs. Medications are typi-
John Wagner cally aimed at amelioration of symptoms, while regenerative medicine
seeks to either recruit the patient’s reparative cells or to replace the mal-
functioning tissue altogether to restore the deficient organ to adequate
SUMMARY function.
Regenerative medicine harnesses the body’s own repair mecha-
Regenerative medicine is a complex and rapidly advancing field that holds nisms to replace, restore, or regenerate damaged or malfunctioning cells
tremendous promise in treating, and even curing, many diseases. The under- and tissues in conditions as diverse as diabetes, heart disease, spinal cord
standing and control of tissue repair is one of the most urgent challenges in injury, and types of blindness. Some regenerative medicine therapies are
medicine today. Regenerative medicine seeks to either recruit the patient’s already in use, for example using unrelated hematopoietic cell trans-
reparative cells or to replace the malfunctioning tissue altogether to restore plant to regenerate a patient’s immune system after their marrow has
the deficient organ to adequate function. The common link among all types been destroyed by chemotherapy or radiation. There are some therapies
of regenerative therapies is the stem cell, which gives all tissues the capacity that are in the early stages of clinical trials, for example using a patient’s
to regenerate. The mechanisms underlying the ability of a progenitor cell to cells seeded onto a biomesh scaffolding to grow a new trachea, ear, or
differentiate have been challenging to elucidate, with recent experimentation nose. Some therapies are on the cusp of progressing into clinical trials,
focused on editing the genome itself. It has been even more difficult to deter- such as differentiating human embryonic stem cells into beta cells that
mine how a differentiated cell can be instructed to revert to an immature state could produce insulin in diabetic patients. And some therapies, such as
and undergo a re-specification to another differentiated cellular phenotype growing new lungs from patient cells and repairing a spinal cord injury
or an asymmetrical division to generate more immature cells. Our ability to with a cellular bridge, remain tantalizingly out of reach.
modify genomes, harness stem cells, and transplant autologous or allogeneic The zygote has the ability to give rise to a complete organism. Any
tissues has transformed biomedical inquiry and offers hope to patients with cellular genome in the organism has the ability to code for any protein
diseases spanning all organ systems, including cardiac, lung, central nervous in the body. Although we know this, the mechanisms underlying the
system, and liver and pancreatic diseases. ability of a progenitor cell to differentiate have been challenging to elu-
cidate. For the earliest critical steps in this long and complex process,
we must look at developmental biology. Nuclear transfers in amphibians
done by Briggs, King, and Gurdon established that bidirectionality of
1–3
cellular fate determination is possible. It was, established by McGrath
Acronyms and Abbreviations: ALS, amyotrophic lateral sclerosis; AMI, and Solter that this process is driven by a multitude of factors of such
acute myocardial infarction; ATI or ATII, alveolar epithelial cells type I or II; temporal and spatial complexity that it would make reprogramming of
4,5
BASCs, bronchiolar alveolar stem cells; BDNF, bone-derived neurotrophic mammalian cells by nuclear transfer impossible. Recent experimen-
factor; BM-derived, marrow-derived; CAR, chimeric antigen receptor; CDCs, tation has focused on editing the genome itself, finding success in both
mouse and human DNA models. Much work remains to bring this tech-
cardiac-derived stem cells; COPD, chronic obstructive pulmonary disease; nology into human therapies, but in the foreseeable future, cells and
CRISPRs, clustered regularly interspaced short palindromic repeats; dmP- organisms will no longer be seen as being given sealed orders at birth,
GE ,16,16-dimethyl-prostaglandin E ; DPSCs, dental pulp stem cells; DSB, but rather the instructions contained in their developmental program
2
2
double-strand break; EC, embryonic carcinoma; ESCs, embryonic stem cells; can be thought of as “software” that can be rewritten and used to repro-
EPCs, epithelial progenitor cells; FAH, fumarylacetoacetate hydrolase; GVHD, gram the genomic “hardware” of a cell.
graft-versus-host disease; HCT, hematopoietic cell transplantation; hESC, It has been even more difficult to imagine and later define the
human embryonic stem cell; HR, homologous recombination; IDLV, possibility that a differentiated cell could be instructed to revert to an
integrase-deficient lentiviral; iPSCs, induced pluripotent stem cells; MN, immature state and undergo a respecification to another differenti-
meganuclease; MNCs, mononuclear cells; MSCs, mesenchymal stromal/stem ated cellular phenotype or an asymmetrical division to generate more
cells; NHEJ, nonhomologous end-joining; NSC, neural stem cell; OPCs, oli- immature cells. Yamanaka’s experimental proof reduced this perceived
godendrocyte progenitor cells; OT, off target; PD, Parkinson disease; SCID-X1, complexity to a four-factor recipe sufficient to restore skin fibroblasts to
X-linked severe combined immunodeficiency; SCNT, somatic cell nuclear induced pluripotent stem cells (iPSCs). 6,7,8
transfer; TALEN, transcription activator-like effector nuclease; TCR, T-cell This chapter gives a broad overview of the state of regenerative
receptor; TGF-β , transforming growth factor-β ; UBCs, umbilical cord blood medicine as it stands today, a complex and rapidly advancing field that
1
1
cells; VEGF, vascular endothelial growth factor; ZFN, zinc finger nuclease. holds tremendous promise in treating, and even curing, many of the
disorders that cause pain and suffering.

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