Commentary: the perspectives of harnessing the power of scattered tubular-like cells for renal repair

Renal regenerative capacity is generally considered limited, especially compared to other tissues like the liver. Nevertheless, it has been recently shown that renal cells have a significant ability to proliferate following injury, highlighting a very intriguing possibility that they can regenerate when prompted by specific conditions. Some studies demonstrate that there are unipotent renal progenitor cells that maintain and self-preserve this organ throughout life [1]. Most research attributes this regenerative response either to the dedifferentiation of mature tubular epithelial cells or to the existence of a resident population of progenitor cells within the kidney [2]. Recent research suggests that the cells involved in kidney regeneration acquire a “progenitor-like” state through dedifferentiation in response to injury rather than possess inherent progenitor characteristics.

A recent review article in Clinical Science (38(15)) by Kazeminia and Eirin [3] describes the mitochondrial function as a crucial mechanism in renal repair and highlighted the potential for new therapies that target mitochondria to improve outcomes of kidney disease. Renal proximal tubules are mitotically quiescent and do not create new daughter cells for regeneration [4]. However, moderate injury of renal tubules can awake the reparative ability and protect renal function to a certain degree. The primary mechanism for this renal tubular regeneration is the replacement of damaged renal epithelial cells by scattered tubular-like cells (STCs), which are renal tubular cells with a progenitor-like function. STCs are characterized by the expression of surface markers CD24 and CD133, also known as heat-stable antigen (HSA) and prominin-1, respectively. CD24 is recognized as a regulator of cell migration and proliferation, while CD133 plays a role in regulating cell senescence [5,6]. These markers contribute to the cells' resistance to pathological stimuli and promote a reparative phenotype, which could also be linked to cancer progression [7]. Upon injury, a subgroup of proximal tubular epithelial cells (PTECs) up-regulates expression of these markers nearly 10-fold, undergoing dedifferentiation to acquire progenitor-like attributes, thereby facilitating the repair of neighboring injured cells [6]. STCs are not a defined population of progenitor cells but rather a type of de-differentiated proximal tubule epithelial cells that show remarkable heterogeneity. STCs contain few mitochondria compared to differentiated tubular epithelial cells and exhibit a glycolytic metabolism [8] instead of relying solely on mitochondrial respiration, which allows them to endure the hypoxic conditions (common to various renal diseases) while they work to locate and repair the affected tissue (Figure 1). This altered metabolic profile was also reported in CD133+ pancreatic tumor cells which have low mitochondrial activity and increased glycolytic pathways and resistance to oxidative stress injury [9]. Unfortunately, STCs can only be harvested via kidney biopsies, as opposed to Endothelial Progenitor Cells (EPC), which can be derived from bone marrow or found in circulation [10], or Mesenchymal Stem/Stromal Cells (MSC), which can be isolated from bone marrow, adipose tissue, placental tissue, etc [11]. Finding healthy kidneys from which to extract viable STCs in sufficient quantity could prove to be a significant limitation. Complicating matters further, STCs comprise a small population of cells within the kidney, so several renal biopsies are required in order to acquire enough STCs to meet therapeutic demands. Unlike progenitor and stem cells, which are known to be present in higher numbers in young tissues, the numbers of STCs in young kidneys are very low [8], making harvesting from a healthy donor challenging. Interestingly, STCs derived from urine and administered to mice with drug-induced focal segmental glomerulosclerosis (FSGS), which causes nephrotic syndrome in children and adults, reduced proteinuria and improved renal function, highlighting urine as a potential source of STCs.

In this commentary, we would like to draw attention to this extremely interesting topic and emphasize the possibilities for future research, as well as current limitations. Recent advancements in our understanding of mitochondrial function reveal their crucial role in determining the fate of renal cells post-injury. The contribution of mitochondria to endogenous renal repair is not uniform; instead, it varies significantly depending on the type and extent of kidney damage, as well as the underlying disease context. Mitochondrial contribution to damage response at the cellular or tissue level varies depending on the type and level of stress, and may include upregulated antioxidant defenses, mitochondrial proliferation, mitochondrial fusion or fission, mitophagy, and initiating apoptotic pathways. In chronic kidney disease (CKD) and hypertension, for example, fission and mitophagy are increased, and in acute kidney injury (AKI), mitochondrial biogenesis is critical to recovery [12–14]. This variability underscores the importance of studying mitochondrial dynamics and their impact on cellular repair processes. One intriguing aspect that remains underexplored is the role of sex differences in mitochondrial function in STCs, and how these differences might influence renal repair mechanisms in males and females. Emerging evidence suggests that mitochondrial function can differ between males and females [15], potentially leading to sex-specific outcomes in kidney regeneration. However, this area of research has been largely overlooked, with most studies failing to account for sex as a biological variable. Given the potential implications for personalized medicine, future research must address this gap, particularly in the context of developing regenerative therapies for kidney disease.

The detection and characterization of STCs have been hindered by the limitations of current techniques, particularly scRNAseq. While scRNAseq has provided valuable insights into general renal gene expression profiles, it struggles to identify rare cell populations such as STCs, especially when they are interspersed among more abundant cell types. Moreover, the inability to discriminate between tubular epithelium proliferation and the preexistence of progenitor cells further complicates our understanding of renal repair mechanisms. This highlights the need for more refined techniques to accurately identify and characterize STCs. A critical consideration in studying renal repair by STCs is the importance of temporal analysis. Current methodologies often rely on snapshot data, which provides limited insight into the dynamic processes underlying kidney regeneration. To truly understand how mitochondrial function influences renal repair, adopting a timeline-based approach that captures the progression of mitochondrial bioenergetic changes in these cells over time is essential. In particular, RNA velocity analyses within proximal tubule cell population before and under stress could provide essential knowledge to describe cell differentiation trajectories and actively transitioned cell states. This will allow for a more comprehensive understanding of the repair process, including identifying key inflection points where therapeutic intervention may be most effective. As highlighted by Kazeminia and Eirin, isolating STCs and delineating their metabolic profiles represent a significant opportunity to unlock new avenues for renal repair. Understanding the metabolic properties of these cells could lead to developing new strategies to induce metabolic reprogramming in regular tubular cells, facilitating their transition to STCs. Such reprogramming could enhance the kidney's regenerative capacity and mitigate maladaptive repair processes contributing to CKD. For instance, abnormal epigenetic memory in mesenchymal stem and progenitor cells, resulting from fetal malnutrition, has been linked to hypertension and renal injury in adulthood - a clear example of how early life events can have long-term consequences for renal health [16].

The kidney's intricate morphological structure suggests the presence of distinct progenitor cell populations that may be selectively activated in response to specific types of injury [17]. Different renal regions, or even individual nephron segments, could harbor unique cell reservoirs contributing to repair processes. It is also plausible that two regeneration mechanisms - proliferation of preexisting cells and recruitment of progenitor cells - coexist within the kidney, complementing each other as needed. For example, the potential for podocyte regeneration and the role of parietal epithelial cells (PECs) as progenitors for both future podocytes and proximal tubular (PT) cells represent exciting areas of investigation [18,19]. The concept of cellular plasticity, where terminally differentiated cells can be reprogrammed to pluripotency or directly to another differentiated cell type, is not limited to in vitro manipulations but extends to the regenerative response to injury in organs. This plasticity allows differentiated adult cells to de-differentiate into a progenitor-like state or trans-differentiate into a different mature cell type, providing a flexible framework for kidney regeneration [18]. Neuronally differentiated macula densa cells, for example, have been shown to regulate tissue remodeling and regeneration in the kidney, further emphasizing the complexity of the regenerative process [20]. Furthermore, CD133 and CD24 markers were identified in progenitor cells within the Bowman's capsule of adult human kidneys, highlighting their diverse potential to differentiate into tubular renal cells or podocytes [21].

Pharmacological interventions also hold promise for enhancing renal regeneration using STCs. For instance, SGLT2 inhibitors have been shown to promote glomerular repopulation by cells of renin lineage in experimental kidney disease [22]. However, the regenerative capacity of the kidney may be limited by factors such as the severity and duration of the injury, as well as the presence of chronic conditions like hypertension or diabetes. While most studies have focused on AKI, it is crucial to investigate whether these regenerative processes differ in the context of long-term injury. The renal microenvironment, including factors such as immunity and oxidative stress, may also play a significant role in modulating mitochondrial function and influencing renal regeneration via STCs. Last, but not least, there is a pressing need to refine the markers used to identify STCs, as current markers like KIM-1 and vimentin lack clear specificity.

In summary, although kidneys do have some regenerative capacity, the extent of renal tissue regeneration depends on the location, nature and severity of the injury. While renal cells have some plasticity and likely can be reprogrammed to aid in tissue repair, and STCs also contribute to the efficiency of the regenerative response upon injury, these intrinsic repair mechanisms are limited, and chronic conditions and severe damage may lead to irreversible lesions and loss of function rather than proper regeneration (Figure 1). Future research in this area should study how to trigger cellular regeneration within different nephron segments and the mechanisms that may limit renal regenerative capacity in various disease states. Metabolic abnormalities and mitochondrial function have emerged as key players in regulating renal cellular function, and special emphasis should be put on the bioenergetic and metabolic signatures of the cells that may be aiding in renal regeneration.

is not applicable as this manuscript does not contain data.

The authors declare no conflicts of interest, financial or otherwise. There were no foreign (non-US) funding sources, in-kind contributions or COIs associated with this study.

This study was supported by R01HL148114, AHA Transformational Project Award 24TPA1283630, and U54HL169191 (to DVI); NIDDK R01DK126720 and U24DK126110 subaward (to OP); and T32HL155011 (supports ACJ, PIs Sullivan/Stepp). Figure was created in Biorender.com.

Adam C. Jones: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. Oleg Palygin: Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Writing—original draft, Writing—review & editing. Daria V. Ilatovskaya: Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Writing—original draft, Project administration, Writing—review & editing.

EPC

endothelial progenitor cell

HSA

heat-stable antigen

MSC

mesenchymal stem/stromal cell

PTEC

proximal tubule epithelial cell

STC

scattered tubular-like cell