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450 Part V: Therapeutic Principles Chapter 30: Regenerative Medicine: Multipotential Cell Therapy for Tissue Repair 451

LUNG REPAIR Although there has been significant preclinical investigation into
The prevalence of lung diseases, like the chronic obstructive pulmonary using EPC and MSC therapy approaches to lung repair, clinical studies
diseases (COPDs) that include asthma and emphysema, has increased have been slow to develop. However, there are a growing number of
dramatically over the last 50 years. Lung disease is expected to become clinical trials in development focused on using MSCs for chronic lung
the third leading cause of disease-related death in the world by 2020. diseases where preclinical data show the most promise. The most recent
New therapeutic approaches from regenerative medicine are being is the PROCHYMAL phase II trial looking at systemic administration
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developed ranging from stem cell therapies to bioengineering of entire of marrow MSCs for moderate to severe COPD, which showed the
tissues of the respiratory system for transplantation. These approaches safety of using MSCs and also preliminary evidence for decrease in
are based on initial observations that endothelial progenitor cells and markers of inflammation.
mesenchymal stem cells can differentiate in vitro to cells expressing lung
epithelial markers and contribute to mature functional bioengineered BRAIN AND SPINAL CORD REPAIR
tissues. Stem cell-based therapy is rapidly developing as a way to improve out-
Throughout the pulmonary tract there exist many different niche comes following brain and spinal cord injury or disease. The human
environments containing distinct epithelial cell types that contribute to CNS is composed of more than 100 billion nerve cells connected in a
the complexity of the lung. Identification of a true endogenous stem complex network that must work seamlessly throughout our lives. Con-
cell population that is responsible for maintaining lung tissue under ditions affecting the CNS—such as stroke, brain, spinal cord injury, and
steady state and injury has been challenging and has been a source of neurodegenerative diseases—affect millions of people worldwide. Chal-
controversy. Evidence from rodent models and human lungs suggests lenges for therapeutic intervention include the complex pathology of
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that the adult endogenous airway, alveolar epithelial cells, lung stroma, these conditions, as well as the specialized anatomical structures of the
and pulmonary vasculature all contain putative stem cell populations CNS that prevent easy access from systemic administration of therapies
that can repair damaged tissue. 76,77 These studies suggest the lung has (e.g., the blood–brain barrier).
a regional hierarchy of stem and progenitor cells that are specific for As with other areas of regenerative medicine, much effort has been
proximal versus distal airways as well as alveoli. spent on the identification of cell types with the best potential for CNS
Identifying endogenous lung stem cells is complex because many repair. Although it was initially thought that the adult CNS did not
different subpopulations of basal epithelial cells exhibit restricted pat- contain progenitor cells for repair, it is now recognized that the human
terns or roles in self-renewal for steady-state maintenance or after CNS does retain an endogenous neural stem cell (NSC) population that
injury. 78,79 In the distal airway, putative progenitor cells have been iden- retains some capacity for repair, although only in select regions and of
tified in the neuroepithelial body, bronchoalveolar duct junction, by a limited nature. Isolated adult and fetal NSCs can be expanded and
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specific markers of self-renewing lung epithelial cells, 82,83 and by func- differentiated into neurons, astrocytes, and oligodendrocytes, the three
tion as bronchiolar alveolar stem cells (BASCs). This is in contrast to main CNS cell types. Adult NSCs are retained throughout life, and are
alveolar epithelial repair thought to be regulated by type 2 alveolar epi- found in the striatal subventricular zone and the dentate gyrus of the
thelial cells (ATII) because they have been shown to be precursors to hippocampus. In preclinical studies, endogenous NSCs have shown
type 1 (ATI) cells. 84,85 Identification of regionally specific stem cell pop- to provide the most significant improvement in functional recovery
ulations is further complicated by the demonstration that isolated distal in rodent stroke models. Isolated human fetal NSCs (CD133+),
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airway progenitors (BASCs, CK5+/p63+) can differentiate into ATII are currently being investigated in a number of clinical studies. 104,105 In
and ATI cells. 86,87 Regardless, all of these cells show unique functions in addition, multiple NSC-based cell therapy trials are being conducted to
repair after injury, reside in different locations in the distal airway and determine the safety and efficacy in patients with amyotrophic lateral
alveolar epithelium, and play different roles as endogenous lung epithe- sclerosis (ALS, sometimes called Lou Gehrig disease). 106,107 Although all
lial progenitors. trials to date have confirmed the safety of using these cells, any benefit
Many preclinical studies have shown that EPCs can increase func- from them has yet to be reported.
tion in pulmonary lung injury models. 88–90 This improvement in func- Although other adult stem cell types (endothelial progenitor cells,
tion could be because of contributions to structure, paracrine effects, umbilical cord blood cells [UBCs], dental pulp stem cells [DPSCs]) have
modulation of immune responses, or a combination of these. EPCs been investigated preclinically, only MSCs have been shown to have the
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have also been demonstrated to preferentially home to sites of injury same level of efficacy as NSCs. Marrow-derived MSCs have been the
in the lung after systemic administration ; consequently, autologous primary focus of preclinical and clinical studies because of their rela-
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EPCs have been used clinically in pulmonary hypertension patients tive abundance and potential for autologous cell transplantation. 108,109
and showed improved cardiopulmonary outcomes. 92,93 Administration of MSCs, regardless of route, have been shown to
Marrow MSCs are known for their immunomodulatory effects in improve outcome measures in rodent models of injury and disease. 106,110
a wide range of diseases. 94,95 The beneficial effect of MSCs results from Based on these findings, there have been a number of early phase clin-
secretion of soluble mediators and microsomal particles that influence ical trials initiated to study the effects of MSC transplantation follow-
lung progenitor cells directly or indirectly through mediation of inflam- ing CNS injury 111,112 or disease. 113,114 In both cases, MSCs have been
matory cells that subsequently promote repair. 96,97 Both preclinical and shown to be both safe and a feasible approach. Although not designed
clinical studies have shown efficacy in either systemic or intratracheal to test efficacy, many trials have observed improvements in functional
administration of MSCs in acute lung injury models, asthma, COPD, outcomes. 115
and a host of other inflammation-related lung injuries or diseases. 75,98 From studies of the efficacy of adult stem cells for therapy in pre-
Although different studies have shown varying degrees of efficacy, there clinical models of CNS injury or disease over the past 20 years, there
are still significant gaps in our understanding of the mechanisms of is strong evidence that transplanted adult stem cells can migrate to the
MSC action on ameliorating disease symptoms and of the specific sub- site of injury and promote functional improvement. The mechanism of
type of MSCs used. This is important, as studies have demonstrated that action, however, remains controversial. There is speculation that the
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certain MSCs can have negative effects in some lung disease models, benefits of cell-based therapy arise from multiple factors. From the host
such as pulmonary fibrosis. 99,100 of preclinical studies on MSCs for treatment of stroke, improvements in

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