Amniotic Fluid Stem Cell Therapy for Lung Disease

Fig. 6.1
Human lung development

Development provides the first context where AFSC-based therapies could prove useful. Many genetic and developmental deficiencies, such as pulmonary hypoplasia, could potentially be addressed in utero, perhaps with the patient’s own AFSC. Furthermore, knowledge of which developmental stage, and what potential genes and pathways are affected are important when attempting to rescue developmental abnormalities later in life.

1.3 Anatomy and Physiology

1.3.1 Macro

Distilled down to its basic function, the lung is designed to serve as a gas exchange system: warming, humidifying and distributing inspired oxygen and eliminating carbon dioxide. The fully developed lung extends from the trachea and terminates in the alveoli. Within the lung there are 23 distinct generations of airways, which serve as distinct functional regions, each of which has evolved to meet specific physiological functions as well as withstand the physical stretch and pressure involved in the process of respiration (Table 6.1) [4].

Table 6.1
Functional regions of the human lung

Anatomical region

Airway generation

Cell populations contained in region




• Ciliated columnar cells

• Warm and humidify inspired air

Main bronchi


• Goblet cells

• Remove inhaled particulates



• Secretory cells

• Turbulent air conduction

• Serous cells

• Brush cells

• Neuroendocrine cells

• Basal cells



• Ciliated cells

• Distribute and deliver inspired air further down respiratory tree

Terminal bronchioles


• Clara cells

Respiratory bronchioles


• Clara cells

• Gas exchange

• Few ciliated cells

• Inhaled particulate clearance
• Air distribution

Alveolar ducts


• Bronchoalveolar stem cells

• Gas exchange

Alveolar sacs

• Type II alveolar epithelial cells

• Type I alveolar epithelial cells

1.3.2 Micro

Although the exact number of distinct cellular phenotypes within the lung is presently unknown, characterizations of populations within the mouse lung have revealed the existence of 40 cell lineages at present [5]. Furthermore, these 40+ lineages are surmised to arise from at least 5 stem/progenitor cellular niches that have been characterized primarily through the use of injury/regeneration models within the adult mouse lung [6]. These niches, outlined in Table 6.2, are the regenerative target in the treatment of lung injury and disease [7]. Recent studies, however, have suggested the involvement of additional stem/progenitor cell populations and mechanisms employed during homeostatic maintenance of the lung [8], such as low density AECII precursors.

Table 6.2
Putative stem/progenitor cell niches within the lung

Cellular niche

Anatomical region

Regenerative capacity

Airway submucosal gland cells (SMG)

Trachea and proximal airways

• Regeneration of tracheal basement membrane and epithelium in a heterotopic syngeneic tracheal transplant mouse model [9]

Tracheal basal cells (keratin 14 expressing)

• Repopulation of tracheal epithelia including ciliated cells and columnar secretory cells following Clara cell specific naphthalene injury [10]

Variant Clara cells–neuroendocrine body (NEB) associated

Distal airways

• Regeneration of airway epithelia following Clara cell depletion [11, 12]

Variant Clara cells–bronchoalveolar duct junction (BADJ) associated

Terminal bronchi

• Regeneration of terminal bronchiolar epithelium following Clara cell depletion [13]

Type II alveolar epithelia (AECII)


• Lineage tracing elucidated self renewal capabilities, ablation of AECII demonstrated clonal expansion and differentiation [14, 15]

Critical to the development of regenerative strategies is an understanding of the regenerative capacity of the lung. Numerous studies have demonstrated the low rate of cell turnover in the lung [16]. Furthermore, the rate of cellular turnover is dependent on architectural region of the lung, with rapid cell turnover observed in the proximal lung and slower turnover in the more distal regions [17]. Consequently, the inherently low regenerative capacity of the lung compounded with the manner of disease or injury in the lung affecting any one of these niches can prove overwhelming for the homeostatic regenerative capacity of the lung.

1.4 Disease and Injury

Disease and injury in the lung can be attributable to genetic abnormalities, such as in the case of patients suffering from cystic fibrosis, or acute or chronic injury and disease, such as disorders resulting from inhalation exposure. As the etiology of many lung diseases, such as idiopathic pulmonary fibrosis, are often poorly understood, determining and treating the root cause of lung dysfunction often becomes secondary to managing and inhibiting disease progression.

Whatever the cause, the first hurdle when treating the lung is understanding the geographical complexity of the affected region. Consequently, this means that multiple cell lineages and niches are likely responsible for repopulating and driving homeostasis in the injured or diseased lung. Compounded with the fact that many of the stem and progenitor cellular niches within the human lung are still not fully characterized, designing effective stem cell-based treatments and therapies to target or repopulate specific cell lineages is quite challenging.

1.5 Current Treatment Strategies

In the case of acute pulmonary injury, such as in acute respiratory distress syndrome, immediate medical and surgical intervention is often necessary. Patients are often monitored closely throughout recovery and respiratory function is often aided through the use of mechanical ventilation or oxygen, which itself can induce injury. In the case of chronic disease or injury, immediate medical intervention does not always occur. The ability for the lung to compensate for loss of function due to injury or disease is tremendous [18, 19]; unfortunately, in the case of many degenerative diseases, once a patient has lost the majority of their lung function, and a diagnosis is finally made, treatment options become quite limited. Palliation of symptoms for patients who are less than ideal candidates for transplantation has become the standard course of treatment. Medications such as corticosteroids, oxygen therapy, and attempts at pulmonary rehabilitation are strategies often employed to further halt the progression of chronic disease. For patients who do receive lung transplants, pharmacologically based anti-rejection therapies must be employed for the remainder of the patient’s life.

1.6 Lung Specific Considerations for Developing Stem Cell-Based Therapies

The disparity of treatment options for lung injury and disease provides ample opportunity for the development of cellular therapies. Furthermore, the magnitude and diversity of injury and disease affecting the lung suggests that cellular therapies for the treatment of respiratory disease will most likely need to encompass a multitude of cell types and approaches to effectively treat specific diseases and specific stages within those diseases [20, 21]. In the lung, both endogenous and exogenous stem cell-based therapies have been investigated with varied success, as summarized in Table 6.3 [14].

Table 6.3
Potential cell populations for the treatment of lung disease



Cell type


Cell type


Niche specific cells (SMG, tracheal basal cells, Clarav, AECII)

• Difficult to culture

Embryonic stem cells

• Form teratomas

• Low isolation yield

• Require differentiation prior to transplant in lung

• Low capacity to differentiate

• Immunomodulatory potential

• Difficult to isolate from patient without invasive procedure

• Must be obtained from donor

Lung stem cells [22]

• Multipotent

Mesenchymal stem cells

• Easy to isolate from patient

• Self renew

• Easy to culture

• Proliferate long term

• Immunomodulatory potential

• Requires further validation

• Can differentiate into various lineages

• Through to contribute to fibrotic disease

Multipotent lung stem cells [23]

• Obtained from homogenized lung

Amniotic fluid stem cells

• Do not form teratomas

• Are in contact with the developing fetal lung

• Niche and functionality still undetermined in vivo

• Immunomodulatory

• Self renew

• Can differentiate into various lineages

• Respond to injured lung milieu

[24, 25]

• Obtained from donor

• Differentiate into specific cell types (AECII and Clara cells)

Once a suitable stem cell-based treatment strategy has been devised, clinicians and scientists must determine appropriate delivery strategies. Cell-based therapies pose an interesting challenge in that, unlike pharmaceuticals, they are dynamic and can be responsive to the environments and conditions to which they are exposed [2430]. Thus, careful consideration must be given to the desired outcome of the stem cell-based treatment, the clinical status of the patient, as well any secondary mechanisms that affect or are employed by the stem cell to ensure appropriate delivery to target locations (Table 6.4).

Table 6.4
Delivery strategies for AFSC into the lung




Must travel through circulation to reach lungs

Deposited directly into lungs

Injected systemically

Minimally invasive

Risk of barotrauma

Minimally invasive

Can be administered without interfering with ventilation machinery

May potentially interfere with ventilation machinery

Can be administered without interfering with ventilation machinery

Minimal propulsory forces exerted on cells

Possibility of shearing upon aerosolization

Minimal propulsory forces exerted on cells

Need for culture prior to injection

Need for culture prior to aerosolization

Need for culture prior to injection

Cell homing to diseased region is possible

Cell homing to diseased region is possible

Cell homing to diseased region is improbable

Thus, taking into account the aforementioned topics of development, anatomy and physiology and variety of diseases affecting the lung, one can begin to understand the complexity of designing any type of cellular therapy for the lung. The varied architecture and variety of cell types and litany of functions performed by these cells suggests that multiple cell types are perhaps required to treat the lung. For example, developmental and genetic abnormalities, such as in cystic fibrosis, resulting in deleterious respiratory phenotypes may require manipulation of stem cells, to overexpress and deliver functional CFTR protein, prior to treatment in order to compensate for endogenous abnormalities. In cases where injury or disease results in the minimal loss of organ function, such as in inhalation exposure, treatment strategies may focus on using stem cells to stimulate endogenous repair mechanisms to improve and promote wound healing. In cases of catastrophic loss of organ function (such as in acute respiratory distress syndrome, ARDS), or progressive disease (as in the case of pulmonary fibrosis), stem cell-based therapies may be useful to inhibit the progression of disease. Finally, in cases where total loss of organ function is inevitable, tissue and organ engineering using stem cells may be a logical treatment strategy. Interestingly, exogenous stem cells have been found within the amniotic fluid that has demonstrated varying levels of success within each of the aforementioned arenas.

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Mar 22, 2018 | Posted by in BIOCHEMISTRY | Comments Off on Amniotic Fluid Stem Cell Therapy for Lung Disease

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