Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 682

may be precursors of SPc + , ScGb1a1 + cells. Very early SPc − progenitor cells

localize to a slightly more proximal position than SPc + cells at the distal tip of the

developing lung.
In adult lungs that undergo slow turnover and possess regenerative capacity
via activation of endogenous stem cell populations, SPc

cells at
the bronchoalveolar junction represent lung epithelial progenitor cells that can
give rise to both alveolar and bronchiolar cell lineages, especially bronchiolar
Clara cells.

+ , ScGb1a1 +

-Catenin controls the balance between progenitor expansion and
epithelial differentiation. During lung epithelium regeneration, the canonical Wnt
pathway is activated in niches at the bronchoalveolar duct junctions that contain
bronchoalveolar stem cells [ 1398 ].
Transcription factor GATA6 synthesized in the respiratory epithelium regulates
the appearance timing and amount of bronchoalveolar stem cells. Its absence causes
the precocious occurrence of bronchoalveolar stem cells and lack in epithelial
differentiation. It activates the synthesis of the epithelial Wnt receptor Frizzled-
2[ 1398 ]. Non-canonical Frizzled-2 receptor precludes early epithelial canonical
Wnt-

β

-catenin signaling. Frizzled-2 also regulates effectors of non-canonical Wnt
signaling, such as G-proteins and calcium-calmodulin-dependent protein kinase
CamK2. Moreover, GATA6 is needed for proper lung epithelial regeneration and
differentiation of bronchoalveolar stem cells.

β

11.3.2.4 P38MAPK

P38 mitogen-activated protein kinase activates transcription factors, such as

CAAT/enhancer-binding protein C/EBPs and Forkhead box protein FoxA2 (a.k.a.
hepatocyte nuclear factor HNF3

α

) that are necessary for the correct differentiation
of the stem cells into alveolar type-2 and Clara cells [ 1399 ]. It controls self-
renewal of the lung stem and progenitor cells, as it coordinates proliferation and
differentiation signals. 5 In particular, it impedes the action of mitogenic factors,
especially epidermal growth factor receptor, hence restraining the proliferation of
stem and progenitor cells.

β

11.3.2.5 Forkhead Box Transcription Factors

Forkhead box protein FoxA2 operates in lung maturation and differentiation of
goblet cells; FoxJ1 in proper development of ciliated cells; and FoxF1 in formation
of pulmonary capillaries.

5 Kinase P38MAPK α also regulates the differentiation and proliferation of myocytes, cardiomy-
ocytes, neurons, adipocytes, and leukocytes. In addition, it prevents the occurence of lung
adenocarcinomas caused by kRas GTPase.