Advancements in lung regeneration: from bench to bedside

Abstract

Lung disorders rank among the leading causes of mortality worldwide, presenting a critical challenge in healthcare. The underlying limited regenerative capacity of the lung makes this an unmet clinical need, often necessitating lung transplantation for patients with severe lung disease. However, the lack of viable donor organs underscores the urgent need for alternative therapeutic strategies. Addressing this challenge requires a comprehensive understanding of the structure of lung tissue and the complexities inherent in its regeneration. In this review, we explore recent breakthroughs in lung regenerative medicine, highlighting innovative approaches aimed at tackling lung and tracheal diseases. From stem cell and cell-based therapies to the utilization of biological and synthetic materials, as well as the strategic deployment of growth factors, a diverse array of strategies is being explored to rejuvenate lung function. By critical analysis of in vitro, preclinical, and clinical studies, this review aims to provide a comprehensive overview of the emerging technology of lung regeneration research, shedding light on promising avenues for future therapeutic interventions.

Keywords: 3D scaffold; Biomaterial; Growth factors; Lung disease; Stem cells; Tissue engineering.

Fig. 1

Mesenchymal stem cells (MSC) can be found in the lungs, and the vascular system is composed of large to smallest blood vessels. The first layer of a three-layered structure is the intima, which has contact with the lumen. The second layer is tunica media, where vascular smooth muscle cells exist and encircle the vascular lumen and create many layers. Finally, it is the outermost adventitia, which interfaces between the vessel wall and around tissues, which is called perivascular space. The perivascular space is not circular compared to the adventitia. It is shown that lung-resident MSCs (LR-MSCs; blue) exist mainly in the wall of the large lung vessels in the adventitia. In this niche, there are other kinds of stem cells, too: HSCs (shown by green cells) and EPCs (indicated by yellow cells). Different MSCs and their relative progenitors reside between endothelial and epithelial cells, and the interstitium space (mesenchyme progenitor cells (PC) is shown by light blue cells) [135]

Fig. 2

Some strategies for creating airway organoids/spheroids. (a) Spheroids can be produced from different organs like nasal polyps or cells from nasal brushing/curettage. They can be grown in liquid media. (b) Differentiated or stem/PCs retrieved from bronchial brushing, nasal or bronchoalveolar lavage (BAL). After induction, they may form spheroids in matrigel. Such spheroids can be generated through 3 methods: [1] After forming the 2D ALI cultures, spheroids will be formed from them; [2] By adding self-renewal cues; [3] The conditioned reprogramming culture (CRC) [136]

Fig. 3

Formation and composition of EVs. (A) Its different shapes are from exosomes (with sizes of up to 150 nm in diameter) and microvesicles (up to 1 nm diameter) to apoptotic bodies (up to 5 μm). EV formations begin from endosomes. They will be transformed into multivesicular bodies (MVBs). They will be fused and degraded with lysosomes, or they will combine with the plasma membrane and turn into intraluminal vesicles, which finally will be released as exosomes. (B) The molecular composition of EVs. They may include HSP proteins, signaling proteins, nucleic acids, enzymes, chaperones, and transcription factors inside them, and immune-interacting molecules, tetraspanins, lipid rafts, and vesicle-trafficking proteins on their surface [137]

Fig. 4

General features of MSCs and their function. (A) The conventional phenotype for identification of MSCs contains the expression of CD90, CD73, and CD105, while without expression of HLA-DR, CD14, CD34, and CD45. MSCs can differentiate in vitro into chondrocytes, adipocytes, and osteoblasts when they are isolated once. (B) The biological activities of MSCs in COVID-19 pneumonia (systemic disease) involve antiviral and immunomodulatory function, differentiation of cells, mesenchymal-epithelial transition (MET), and angiogenesis, which is due to therapeutic activity and the paracrine secretion of soluble factors (so-called secretome) [91]

Fig. 5

Strategies of MSC production on the basis of MSC sources, the system utilized for in vitro proliferation, final products for ARDS treatment, and culture cell conditions [95]