Lung Regeneration

In above sections, we have briefly discussed the understanding of normal lung development along with some of the major lung disorders that are known to have high prevalence globally. This discussion will help in making a better prospect of strategies that are being used and/or required in future for rebuilding or regeneration of lung for advanced treatment approaches of various lung diseases.

Stem and/or Progenitor Cells for Lung Regeneration

The progenitor cells are primarily present in bone marrow that further help in the generation of various cell lines, these progenitor cells include hematopoietic stem cells, fibroblasts, and/or mesenchymal stem cells (Jones et al. 2009). These progenitor cells have been reported to help in modifying various organ disorders like lung diseases and liver disorders. Interestingly, other than bone marrow, lungs themselves have been reported to possess progenitor cells, including conducting airway stem cells and distil lung epithelial progenitor cells (Rock and Konigshoff 2012). Nevertheless, various studies have varying suggestions regarding the role of progenitor cells in lung regeneration for diseased lung. The details of different experimental studies have been identified in Table 7.2 (Neuringer and Randell

2004) for delivery of lung progenitor cells either having positive or negative results. Moreover, circulating endothelial progenitor cells (EPCs) have been used experimentally to observe their repairing effects on damaged lung vasculature. Further EPCs are known to be helpful in future for pulmonary hypertension. Similarly, when investigated, bone marrow-derived mesenchymal stromal cells (MSCs) have also shown their immunomodulatory effects in lung disease suggesting their future role for the treatment of particular lung disorders like COPD (Lau et al. 2012). As in COPD there occurs loss of proteolytic lung parenchyma and elastic recoil, so use of stem cells rather than drug therapy which can only provide symptomatic relief might be more beneficial. Alveolar type II pneumocytes are well known to have the ability to repair any damage to alveoli, it has been reported that human embryonic stem cells can be transformed into alveolar type II pneumo- cytes (Wang et al. 2007).

Similarly, the growing literature has provided an evidence for the potential of cell-based therapy for ARDS in particularly MSCs (Matthay et al. 2010). It has been reported that bleomycin-induced liver damage in mice was significantly decreased by the utilization of MSCs (Ortiz et al. 2003). Moreover, the response of host towards bacterial sepsis has also been observed to be improved after the use of MSCs by the reduction of septic lung damage (Gupta et al. 2007; Danchuk et al. 2011).

Fibroblast growth factor (FGF)-10, which is known to regulate early lung epithelial progenitor cells, is known to be secreted by MSCs that are at the distal tip of the branching epithelium (Ramasamy et al. 2007). FGF-10 is also important for signal pathways (Bmp, Wnt, and Shh) involved controlling progenitor cells for lung development (Morrisey and Hogan 2010). Similarly, bronchiolar smooth muscles are reported to be generated through MSCs adjacent to the trachea and extrapulmonary bronchi (Shan et al. 2008). Moreover, the expression of genes of induced pluripo- tent stem cells (iPSCs) are comparable to ESCs and there is a growing evidence of utilization of iPSCs against ARDS as shown in Fig. 7.3 (Hayes et al. 2012). Interestingly, recently c-kit-positive cells found in distal lung of human have been tried for injured mouse cells showing significant lung regeneration (Kajstura et al.

2011). However, more work is required to elucidate the precise mechanism of these c-kit-positive cells and their role in lung regeneration.

Table 7.2 Acute respiratory distress syndrome (ARDS)

Study

Disease model

Tissue of origin

Lung cell type formed

Method of detection

Animal

BMT

MSC

Undefined mesenchymal cells

PCR for collagen gene marker

Animal

Bleomycin fibrosis

MSC

Type I pneumocytes

B-galactosidase protein

Animal

BMT

HSC enrichment

Type II pneumocytes/up to 20%, bronchial epithelium/4 %

Y chromosome FISH, surfactant В mRNA

Animal

Radiation pneumonitis

Whole bone marrow

Type II pneumocytes, bronchial epithelium/up to 20 % of type II cells

Y chromosome FISH, surfactant В mRNA

Animal

BMT

Whole bone marrow/ EGFP retrovirus

Type II pneumocytes/1-7 %

EGFR keratin immunostain, surfactant protein В FISH

Animal

BMT and parabiotic Animals

HSC

Hematopoietic chimerism but exceedingly rare lung cell types

EGFP

Animal

Bleomycin fibrosis

MSC

Type II pneumocytes/~l %

Y chromosome FISH

Animal

Radiation fibrosis

MSC or whole bone marrow

Fibroblasts

EGFR Y chromosome FISH, vimentin immunostain

Animal

BMT

Bone marrow, EGFP labeled

Fibroblasts, type I pneumocyte

Flow cytometry

Animal

Hypoxia-induced

pulmonary

hypertension

Circulating BM-derived c-kit positive

c-kit positive cells in pulmonary artery vessel wall; In hypoxia, circulating cells generate endothelial and smooth muscle cells in-vitro

Flow cytometry and immunohistochemistry

Animal

Ablative radiation and elastase induced emphysema

GFP+ fetal liver

Alveolar epithelium and endothelium; frequency not reported but increased by G-CSF and retinoic acid

Immunohistochemistry for CD45-, GFP+ cells

Animal

Bleomycin fibrosis

Whole marrow GFP+

GFP+ type I collagen expressing

Flow cytometry and immunohistochemistry, RT-PCR

Human

Heat shock in cell culture

MSC and SAEC

Cell fusion

Immunostaining, microarray

Animal and human

OVA-sensitized mouse model, allergen- sensitized asthmatics

CD34 positive, collagen I expressing librocytes CD34 positive, collagen I expressing librocytes

Myofibroblasts

CD34-positive, collagen I. а-smooth muscle actin CD34-positive, collagen I. a-smooth muscle actin

Human

Human heart and lung transplant

Sex-mismatched donor lung or heart

No lung cell types of recipient origin

X and Y chromosome FISH, antibody stain for hematopoietic cells

Human

Human lung transplant, human BMT

Sex-mismatched donor lung and sex-mismatched donor bone marrow

Bronchial epithelium, type II pneumocytes, glands of recipient origin

No lung cell types of donor origin

Y chromosome FISH, short tandem repeat PCR

Y chromosome FISH, short tandem repeat PCR

Human

Human BMT

Sex-mismatched donor bone marrow

Lung epithelium and endothelium of donor origin

X and Y chromosome FISH, keratin, and PECAM immunostain

Human

Human BMT

Sex-mismatched donor bone marrow

No nasal epithelium of donor origin

Y chromosome FISH, cytokeratin immunostain

Reproduced with permission from Ref. Neuringer and Randell (2004)

BMTbone marrow transplant (with prior ablation). MSC mesenchymal stem cells (bone marrow stromal cells, adherent bone marrow cells). EGFP enhanced green fluorescent protein. HSC hematopoietic stem cells. FISH fluorescence in situ hybridization. SAEC small airway epithelial cells

128

K. Rehman and M.S.H. Akash

Potential applications of induced pluripotent stem cells for liver diseases

Fig. 7.3 Potential applications of induced pluripotent stem cells for liver diseases: Reproduced with permission from Ref. Hayes et al. (2012)

Various types of pathogenic mechanisms are involved in different types of lung diseases that have been briefly described in the above sections, but for the utilization of safe and effective cell-based treatments for these diseases, use of exogenous stem/ progenitor cells is very essential to find out the probable chances for the development of further complications.

 
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